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Msg  10306 of 10558  at  9/22/2022 9:34:12 AM  by

JBWIN


Building IP: JUNO Patent Appl. re "COMBINATION THERAPY OF A T CELL THERAPY AND AN

 
United States Patent Application20220298222
Kind CodeA1
CHANG; Henry ; et al.September 22, 2022

COMBINATION THERAPY OF A T CELL THERAPY AND AN ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR AND RELATED METHODS

Abstract

Provided are methods, uses, and articles of manufacture of combination therapies involving immunotherapies and cell therapies, such as adoptive cell therapy, e.g. a T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2), for treating subjects having or suspected of having a cancer, and related methods, uses, and articles of manufacture. The T cell therapy includes cells that express recombinant receptors such as chimeric antigen receptors (CARs).


Inventors:CHANG; Henry; (Summit, NJ) ; FILVAROFF; Ellen; (Summit, NJ) ; FOX; Brian; (Seattle, WA) ; MOHAN; Adithi; (Summit, NJ) ; NEWHALL; Katie; (Seattle, WA) ; OLSON; Nels Eric; (Seattle, WA)
Applicant:
NameCityStateCountryType

Juno Therapeutics, Inc.

Seattle

WA

US
Assignee:Juno Therapeutics, Inc.
Seattle
WA

Family ID:1000006432172
Appl. No.:17/636181
Filed:August 21, 2020
PCT Filed:August 21, 2020
PCT NO:PCT/US2020/047537
371 Date:February 17, 2022

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
63037584Jun 10, 2020
63024502May 13, 2020
62890607Aug 22, 2019

Current U.S. Class:1/1
Current CPC Class:C07K 2319/03 20130101; C07K 2317/24 20130101; A61P 35/00 20180101; C07K 14/7051 20130101
International Class:C07K 14/725 20060101 C07K014/725; A61P 35/00 20060101 A61P035/00

Claims



1. A method of treating cancer, the method comprising: (1) administering to a subject having a cancer a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer; and (2) administering to the subject an inhibitor of enhancer of zeste homolog 2 (EZH2).

2. A method of treating cancer, the method comprising administering to a subject having a cancer an inhibitor of enhancer of zeste homolog 2 (EZH2), wherein the subject is a candidate for being administered or has been administered a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen associated with, expressed by, or present on cells of the cancer.

3. A method of treating a cancer in a subject, the method comprising administering a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR) to a subject having a cancer, wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, wherein the subject has been administered or is to be administered an inhibitor of enhancer of zeste homolog 2 (EZH2).

4. A method of treating a cancer with a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method comprising: (a) assessing in a tumor biopsy sample from a subject: (i) the level or amount of one or more first gene selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; (b) selecting the subject for treatment with the cell therapy if: (i) the level or amount of the one or more first gene is below a gene reference value; and/or (ii) the level or amount of the one or more second gene is above a gene reference value; and (c) administering to the selected subject the T cell therapy.

5. A method of treating a cancer with an inhibitor of enhancer of zeste homolog 2 (EZH2) and a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method comprising: (a) assessing in a tumor biopsy sample from a subject: (i) the level or amount of one or more first gene selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; (b) selecting the subject for treatment if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value; and (c) administering to the selected subject the EZH2 inhibitor and the T cell therapy.

6. A method of selecting a subject having a cancer for administration of an enhancer of zeste homolog 2 (EZH2) inhibitor, the method comprising: (a) assessing (i) the level or amount of one or more first gene in a tumor biopsy sample from the subject selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene in a biological sample from the subject, selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; the subject is to receive administration of a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, and the tumor biopsy sample is obtained from the subject prior to the administration of the cell therapy; and (b) selecting the subject having the cancer for treatment with the EZH2 inhibitor and the cell therapy if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value.

7. The method of claim 6, wherein, if the subject is selected for treatment with the EZH2 inhibitor, the method further comprises administering to the selected subject the EZH2 inhibitor and the T cell therapy.

8. The method of claim 6, wherein, if the subject is not selected for treatment with the EZH2 inhibitor, the method comprises only administering only the T cell therapy to the subject.

9. The method of any of claims 4-8, wherein the gene reference value is within 25%, within 20%, within 15%, within 10%, or within 5% of an average level or amount of the one or more gene in (a) a population of subjects not having the cancer or (b) a population of subjects having the cancer and administered the T cell therapy, who went on to exhibit a partial response (PR) or complete response (CR) following administration of the T cell therapy.

10. The method of claim 9, wherein the population of subjects having the cancer went on to exhibit PR or CR at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or more following administration of the T cell therapy.

11. A method of treating a cancer with a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method comprising: (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from a subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2; (b) selecting the subject for treatment with the cell therapy if: (i) the expression of the one or more first gene set is downregulated; and/or (ii) the expression of the one or more second gene set is upregulated; and (c) administering to the selected subject the T cell therapy.

12. A method of treating a cancer with an inhibitor of enhancer of zeste homolog 2 (EZH2) and a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method comprising: (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from a subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2; (b) selecting the subject for treatment with the EZH2 inhibitor and the cell therapy if: (i) the expression of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated; and (c) administering to the selected subject the EZH2 inhibitor and the T cell therapy.

13. A method of selecting a subject having a cancer for administration an enhancer of zeste homolog 2 (EZH2) inhibitor, the method comprising: (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2, wherein the subject is to receive administration of a T cell therapy comprising T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, and the tumor biopsy sample is obtained from the subject prior to the administration of the cell therapy; and (b) selecting the subject having the cancer for treatment with the EZH2 inhibitor and the T cell therapy if: (i) the expression of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated.

14. The method of any of claims 1-13, wherein the T cell therapy comprises cells that are autologous to the subject.

15. The method of any of claims 1-14, wherein, prior to administering the T cell therapy to the subject, producing the T cell therapy ex vivo from autologous cells from a biological sample collected from the subject, optionally wherein the biological sample is or comprises an apheresis product.

16. The method of claim 15, wherein the T cells of the T cell therapy are derived from the autologous cells of the biological sample.

17. The method of any of claims 1-16, wherein the subject is administered a lymphodepleting therapy prior to initiation of administration of the T cell therapy.

18. The method of any of claims 15-17, wherein the subject is administered a lymphodepleting therapy after collection of the biological sample and prior to initiation of administration of the EZH2 inhibitor and/or the T cell therapy.

19. The method of claim 17 or claim 18, wherein the lymphodepleting therapy concludes between 2 and 7 days before initiation of administration of the T cell therapy.

20. The method of any of claims 4-19, wherein the tumor biopsy sample is obtained before a lymphodepleting therapy is administered to the subject, optionally within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

21. The method of any of claims 17-20, wherein the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy, optionally wherein the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy.

22. The method of any of claims 17-21, wherein the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy, optionally wherein administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

23. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-22, wherein the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor prior to initiation of administration of the T cell therapy.

24. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-23, wherein the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor between about 4 weeks prior to initiation of administration of the T cell therapy and about 1 week prior to initiation of administration of the T cell therapy.

25. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-20, and 22, wherein the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the inhibitor at a time between at or about 14 days, at or about 7 days, or at or about 1 day prior to and at or about 14 days, at or about 7 days, or at or about 1 day after initiation of administration of the T cell therapy.

26. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-25, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 2 days prior to initiation of administration of the T cell therapy.

27. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-26, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor at or about 7 days, at or about 5 days, at or about 3 days, at or about 2 days, or at or about 1 day prior to initiation of administration of the T cell therapy.

28. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-27, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor within about or about 5 days prior to initiation of administration of the T cell therapy.

29. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-28, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor within about or about 2 days prior to initiation of administration of the T cell therapy.

30. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-29, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor within about or about 1 day prior to initiation of administration of the T cell therapy.

31. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-30, wherein the EZH2 inhibitor is administered in a dosing regimen comprising: initiation of administration of the inhibitor concurrent with or on the same day as initiation of administration of the T cell therapy; and/or administration of at least one dose of the EZH2 inhibitor concurrently with the T cell therapy and/or on the same day as the T cell therapy.

32. The method of any of claims 3, 5, 7, 9, 10, 12, and 13-31, wherein the EZH2 inhibitor is administered in a dosing regimen comprising initiation of administration of the inhibitor no more than 2 days after initiation of administration of the T cell therapy, optionally wherein the dosing regimen comprises initiation of administration of the inhibitor within 1 day after the initiation of administration of the T cell therapy.

33. The method of any of claims 3, 5, 7, 9, 10, 12, 13-30, and 32, wherein the EZH2 inhibitor is administered in a dosing regimen comprising ceasing administration of the EZH2 inhibitor at least 7 days before, at least 5 days before, at least 2 days before, or at least 1 day before initiation of administration of the T cell therapy.

34. The method of any of claims 1-33, wherein administration of the T cell therapy comprises administration of between about 1.times.10.sup.5 total CAR-expressing T cells and about 5.times.10.sup.8 total CAR-expressing T cells.

35. The method of any of claims 1-34, wherein the T cell therapy is enriched in CD3+, CD4+, CD8+ or CD4+ and CD8+ T cells.

36. The method of any claims 1-35, wherein the T cell therapy is enriched in CD4+ and CD8+ T cells.

37. The method of claim 36, wherein the CD4+ and CD8+ T cells of the T cell therapy comprises a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells and/or of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells, that is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1.

38. The method of any of claims 1-37, wherein the CAR comprises an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM.

39. The method of any of claims 1-38, wherein the antigen is a B cell antigen, optionally wherein the antigen is selected from among CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30

40. The method of claim 38 or claim 39, wherein the intracellular signaling domain comprises an intracellular domain of a CD3-zeta (CD3.zeta.) chain.

41. The method of any of claims 38-40, wherein the intracellular signaling region further comprises a costimulatory signaling region.

42. The method of claim 41, wherein the costimulatory signaling region comprises a signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB.

43. The method of any of claims 17-42, wherein the lymphodepleting therapy comprises administration of fludarabine and/or cyclophosphamide.

44. The method of any of claims 17-43, wherein: (i) the lymphodepleting therapy comprises administration of cyclophosphamide at about 200-400 mg/m.sup.2, optionally at or about 300 mg/m.sup.2, inclusive, and/or fludarabine at about 20-40 mg/m.sup.2, optionally 30 mg/m.sup.2, daily for 2-4 days, optionally for 3 days, or wherein the lymphodepleting therapy comprises administration of cyclophosphamide at about 500 mg/m.sup.2; and/or (ii) the lymphodepleting therapy comprises administration of cyclophosphamide at or about 300 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days; and/or the lymphodepleting therapy comprises administration of cyclophosphamide at or about 500 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days.

45. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-44, wherein the EZH2 inhibitor is administered in a dosing regimen comprising administration of about 800 mg of the inhibitor per day.

46. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-44, wherein the EZH2 inhibitor is administered in a dosing regimen comprising administration of about 1600 mg of the inhibitor per day.

47. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-44, wherein the EZH2 inhibitor is administered in a dosing regimen comprising administration of about 2400 mg of the inhibitor per day.

48. The method of any of claims 1-3, 5, 7, 9, 10, 12, and 13-44, wherein the inhibitor is administered in a dosing regimen comprising one or more doses of the inhibitor, and a dose is between at or about 200 mg and at or about 1600 mg.

49. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-44, and 48, wherein the EZH2 inhibitor is administered in a dosing regimen that comprises two doses each day (twice daily dosing).

50. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-44, and 48, wherein the inhibitor is administered in a dosing regimen that comprises three doses each day (thrice daily dosing).

51. The method of any of claims 48-50, wherein each dose of the inhibitor is between at or about 400 mg and at or about 800 mg, inclusive.

52. The method of any of claims 48-51, wherein each dose of the inhibitor is at or about 400 mg.

53. The method of any of claims 48-51, wherein each dose of the inhibitor is at or about 800 mg.

54. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-32, and 34-53, wherein the EZH2 inhibitor is administered in a dosing regimen comprising administration of the EZH2 inhibitor, optionally two times daily or three times daily, for up to three months after the initiation of administration of the cell therapy.

55. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-32, and 34-54, wherein the dosing regimen comprises administration of the EZH2 inhibitor, optionally two times daily or three times daily, for up to two months after the initiation of administration of the cell therapy.

56. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-32, and 34-55, wherein the dosing regimen comprises administration of the EZH2 inhibitor, optionally twice daily or three times daily, for up to 1 month after the initiation of administration of the cell therapy.

57. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-32, and 34-53, wherein the dosing regimen comprises administration of the EZH2 inhibitor, optionally twice daily or three times daily, until the subject exhibits a complete response or until the subject exhibits disease progression.

58. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-32, and 34-53, wherein the dosing regimen comprises discontinuing administration of the EZH2 inhibitor if the subject exhibits clinical remission.

59. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-58, wherein the EZH2 inhibitor is selected from among the group consisting of tazemetostat (EPZ-6438), CPI-1205, GSK343, GSK126, and valemetostat (DS-3201b).

60. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-59, wherein the EZH2 inhibitor is tazemetostat (EPZ-6438).

61. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-59, wherein the EZH2 inhibitor is CPI-1205.

62. The method of any of claims 1-61, wherein the cancer is a solid tumor.

63. The method of any of claims 1-61, wherein the cancer is a hematological malignancy.

64. The method of any of claims 1-61 and 63, wherein the cancer is a B cell malignancy.

65. The method of any of claims 1-61, 63, and 64, wherein the cancer is a myeloma, leukemia, or lymphoma.

66. The method of any of claims 1-61 and 63-65, wherein the cancer is an acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), a small lymphocytic lymphoma (SLL), a non-Hodgkin lymphoma (NHL), or a large B cell lymphoma.

67. The method of any of claims 1-61 and 63-66, wherein the cancer is a non-Hodgkin lymphoma (NHL).

68. The method of claim 67, wherein the NHL is a diffuse large B-cell lymphoma (DLBCL), optionally a germinal center B-cell (GCB) subtype of DLBCL.

69. The method of any of claims 1-3, 5, 7, 9, 10, 12, 13-68, comprising selecting the subject for treatment with the EZH2 inhibitor as a subject that has a DLBCL, optionally a germinal center B-cell (GCB) subtype of DLBCL.

70. The method of any of claims 1-69, wherein the subject has relapsed following remission after treatment with, or become refractory to, failed and/or was intolerant to treatment with a prior therapy for treating the cancer.

71. The method of any of claims 1-70, wherein the cancer is resistant to treatment with the T cell therapy alone.

72. The method of any of claims 1-71, wherein: the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject; and/or in a plurality of subjects treated, infiltration of the CAR-expressing T cells of the cell therapy into a tumor microenvironment (TME) is increased, compared to a method that does not involve the administration of the inhibitor.

73. The method of any one of claims 1-72, wherein the tumor biopsy sample is a lymph node biopsy.

74. The method of any one of claims 1-73, wherein the subject is a human.

75. The method of any of claims 4-10 and 14-74, wherein the level or amount of the one or more gene is the level or amount of a polynucleotide encoded by the one or more gene.

76. The method of any of claims 4-10 and 14-75, wherein the one or more first gene is EZH2.

77. The method of any of claims 4-10 and 14-76, wherein the one or more first gene is selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); transferrin receptor (TFRC); minichromosome maintenance complex component 2 (MCM2); enolase 1, (alpha) (ENOL); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); intercellular adhesion molecule 1 (ICAM1); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (MTHFD1); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); solute carrier family 1 (neutral amino acid transporter), member 5 (SLC1A5); mitochondrial ribosomal protein L4 (MRPL4); nicotinamide phosphoribosyltransferase (NAMPT); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); vascular endothelial growth factor A (VEGFA); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); dual specificity phosphatase 1 (DUSP1); cyclin-dependent kinase 2 (CDK2); exportin 5 (XPO5); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); solute carrier family 43, member 3 (SLC43A3); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); solute carrier family 39 (zinc transporter), member 8 (SLC39A8); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); perilipin 2 (PLIN2); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); mitogen-activated protein kinase 13 (MAPK13); transgelin 2 (TAGLN2); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); activating transcription factor 3 (ATF3); immediate early response 5 (IER5); transketolase (TKT); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); solute carrier family 3 (amino acid transporter heavy chain), member 2 (SLC3A2); flap structure-specific endonuclease 1 (FEN1); activating transcription factor 5 (ATFS); fatty acid synthase (FASN); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); germ cell associated 2 (haspin) (GSG2); jun proto-oncogene (JUN); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); uridine phosphorylase 1 (UPP1); kinesin family member 18B (KIF18B); kelch-like family member 23 (KLHL23); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); ubiquitin-like with PHD and ring finger domains 1 (UHRF1); and combinations thereof.

78. The method of any of claims 4-10 and 14-77, wherein the one or more first gene is selected from the group consisting of selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); minichromosome maintenance complex component 2 (MCM2); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); flap structure-specific endonuclease 1 (FEN1); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); kinesin family member 18B (KIF18B); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); ubiquitin-like with PHD and ring finger domains 1 (UHRF1); and combinations thereof.

79. The method of any one of claims 4-10 and 14-78, wherein the one or more first gene is selected from the group consisting of: MCM3, CENPM, TRIP13, UBE2S, SPC24, CDC25A, RFC3, ASF1B, H2AFX, DDX39A, GINS1, UBE2T, POLD1, TK1, CDK4, RNASEH2A, KIF18B, DNMT1, ESPL1, SNRPB, MCM3, CDC6, UBE2S, CDC25A, H2AFX, DDX39A, CDK4, E2F2, RAD54L, E2F1, ESPL1, MCM2, GINS2, POLQ, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, CDK1, EBP, SLC1A5, CDC25A, DDX39A GLA, STC1, MCM2 RRM2, HSPE1, ACLY, TMEM97, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, CDK4, HSPE1, FARSA, TMEM97, MCM4, UNG, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof.

80. The method of any of claims 4-10 and 14-79, wherein the one or more second gene is a T cell marker, optionally CD3.epsilon..

81. The method of any of claims 4-10 and 14-80, wherein the one or more second gene is selected from the group consisting of: KLRB1, CD40LG, ICOS, CD28, CCL21, and combinations thereof.

82. The method of any of claims 4-10 and 14-81, wherein the one or more second gene is selected from the group consisting of: PDCD1, LAG3, TIGIT, and combinations thereof.

83. The method of any of claims 4-10 and 14-82, wherein the one or more second gene is selected from the group consisting of: FYN, TXK, ZBP1, TMEM71, KIAA1551, and combinations thereof.

84. The method of any one of claims 4-10 and 14-83, wherein the one or more second gene is selected from the group consisting of: calcium channel, voltage-dependent, alpha 2/delta subunit 2 (CACNA2D2); aminoadipate-semialdehyde synthase (AASS); teneurin transmembrane protein 1 (TENM1); TRAF3 interacting protein 3 (TRAF3IP3); FYN oncogene related to SRC, FGR, YES (FYN); CD6 molecule (CD6); protein kinase C, eta (PRKCH); ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 2 (ARAP2); protein kinase C, theta (PRKCQ); interaction protein for cytohesin exchange factors 1 (IPCEF1); TXK tyrosine kinase (TXK); Rho GTPase activating protein 15 (ARHGAP15); trinucleotide repeat containing 6C (TNRC6C); transcription factor 7 (T-cell specific, HMG-box) (TCF7); cholesteryl ester transfer protein, plasma (CETP); signal-regulatory protein gamma (SIRPG); ring finger protein 125, E3 ubiquitin protein ligase (RNF125); CD40 ligand (CD40LG); RNA polymerase I transcription factor homolog (S. cerevisiae) pseudogene 2 (RRN3P2); olfactomedin 2 (OLFM2); GATA binding protein 3 (GATA3); cubilin (intrinsic factor-cobalamin receptor) (CUBN); sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2 (SPOCK2); inositol polyphosphate-4-phosphatase, type II, 105 kDa (INPP4B); CD5 molecule (CD5); ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (ST8SIA1); complement component 7 (C7); IL2-inducible T-cell kinase (ITK); leukemia inhibitory factor receptor alpha (LIFR); phospholipase C-like 1 (PLCL1); CD2 molecule (CD2); cyclin D2 (CCND2); clusterin (CLU); Z-DNA binding protein 1 (ZBP1); B-cell CLL/lymphoma 11B (zinc finger protein) (BCL11B); chimerin 1 (CHN1); catsper channel auxiliary subunit beta (CATSPERB); interleukin 6 signal transducer (gp130, oncostatin M receptor) (IL6ST); chemokine (C-C motif) ligand 21 (CCL21); phospholipase C, beta 2 (PLCB2); signal transducer and activator of transcription 4 (STAT4); killer cell lectin-like receptor subfamily G, member 1 (KLRG1); solute carrier family 12 (potassium/chloride transporter), member 6 (SLC12A6); fibulin 7 (FBLN7); sex comb on midleg-like 4 (Drosophila) (SCML4); solute carrier family 22 (organic cation transporter), member 3 (SLC22A3); G protein-coupled receptor 174 (GPR174); tetratricopeptide repeat domain 12 (TTC12); phospholipase C, eta 2 (PLCH2); coiled-coil domain containing 102B (CCDC102B); cysteinyl leukotriene receptor 2 (CYSLTR2); N-myristoyltransferase 2 (NMT2); CD8a molecule (CD8A); ankyrin repeat domain 29 (ANKRD29); tetratricopeptide repeat domain 39B (TTC39B); ADAM metallopeptidase with thrombospondin type 1 motif, 3 (ADAMTS3); synaptic vesicle glycoprotein 2A (SV2A); ubiquitin associated and SH3 domain containing A (UBASH3A); vascular cell adhesion molecule 1 (VCAM1); transforming growth factor, beta receptor II (70/80 kDa) (TGFBR2); T cell receptor associated transmembrane adaptor 1 (TRAT1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4); inducible T-cell co-stimulator (ICOS); CD200 receptor 1 (CD200R1); protein tyrosine phosphatase, non-receptor type 13 (APO-1/CD95 (Fas)-associated phosphatase) (PTPN13); deoxyribonuclease I-like 3 (DNASE1L3); coagulation factor II (thrombin) receptor-like 2 (F2RL2); acyl-CoA synthetase long-chain family member 6 (ACSL6); sterile alpha motif domain containing 3 (SAMD3); potassium channel, subfamily K, member 5 (KCNK5); transmembrane protein 71 (TMEM71); tandem C2 domains, nuclear (TC2N); schlafen family member 5 (SLFN5); eva-1 homolog C (C. elegans) (EVA1C); small G protein signaling modulator 1 (SGSM1); CD3d molecule, delta (CD3-TCR complex) (CD3D); ATP-binding cassette, sub-family A (ABC1), member 3 (ABCA3); G protein-coupled receptor 183 (GPR183); ankyrin repeat and kinase domain containing 1 (ANKK1); olfactory receptor, family 2, subfamily A, member 20 pseudogene (OR2A20P); sphingosine-1-phosphate receptor 1 (S1PR1); zinc finger protein 483 (ZNF483); chemokine (C motif) receptor 1 (XCR1); CD7 molecule (CD7); KIAA1551 (KIAA1551); glucosaminyl (N-acetyl) transferase 4, core 2 (GCNT4); potassium voltage-gated channel, shaker-related subfamily, member 2 (KCNA2); CD28 molecule (CD28); GTPase, IMAP family member 7 (GIMAP7); ankyrin repeat domain 18A (ANKRD18A); T cell immunoreceptor with Ig and ITIM domains (TIGIT); chemokine (C-C motif) receptor 4 (CCR4); SH2 domain containing 1A (SH2D1A); interleukin 3 receptor, alpha (low affinity) (IL3RA); GPRIN family member 3 (GPRIN3); ecotropic viral integration site 2B (EVI2B); nucleosome assembly protein 1-like 2 (NAP1L2); selectin L (SELL); death domain containing 1 (DTHD1); C-type lectin domain family 4, member C (CLEC4C); alpha-kinase 2 (ALPK2); CD3e molecule, epsilon (CD3-TCR complex) (CD3E); l(3)mbt-like 3 (Drosophila) (L3MBTL3); arrestin domain containing 5 (ARRDC5); linker for activation of T cells (LAT); protein associated with topoisomerase II homolog 2 (yeast) (PATL2); A2M antisense RNA 1 (A2M-AS1); LINC01550 (LINC01550); GTPase, very large interferon inducible pseudogene 1 (GVINP1); long intergenic non-protein coding RNA 239 (LINC00239); and combinations thereof.

85. The method of any of claims 4-10 and 14-84, wherein the one or more second gene is selected from the group consisting of: LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof.

86. The method of any of claims 11-74, wherein the one or more first gene set comprises a plurality of genes selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); minichromosome maintenance complex component 2 (MCM2); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); flap structure-specific endonuclease 1 (FEN1); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); kinesin family member 18B (KIF18B); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); and ubiquitin-like with PHD and ring finger domains 1 (UHRF1).

87. The method of any of claims 11-74 and 86, wherein the one or more first gene set comprises a plurality of genes selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); transferrin receptor (TFRC); minichromosome maintenance complex component 2 (MCM2); enolase 1, (alpha) (ENO1); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); intercellular adhesion molecule 1 (ICAM1); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (MTHFD1); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); solute carrier family 1 (neutral amino acid transporter), member 5 (SLC1A5); mitochondrial ribosomal protein L4 (MRPL4); nicotinamide phosphoribosyltransferase (NAMPT); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); vascular endothelial growth factor A (VEGFA); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); dual specificity phosphatase 1 (DUSP1); cyclin-dependent kinase 2 (CDK2); exportin 5 (XPO5); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); solute carrier family 43, member 3 (SLC43A3); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); solute carrier family 39 (zinc transporter), member 8 (SLC39A8); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); perilipin 2 (PLIN2); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); mitogen-activated protein kinase 13 (MAPK13); transgelin 2 (TAGLN2); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); activating transcription factor 3 (ATF3); immediate early response 5 (IER5); transketolase (TKT); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); solute carrier family 3 (amino acid transporter heavy chain), member 2 (SLC3A2); flap structure-specific endonuclease 1 (FEN1); activating transcription factor 5 (ATFS); fatty acid synthase (FASN); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); germ cell associated 2 (haspin) (GSG2); jun proto-oncogene (JUN); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); uridine phosphorylase 1 (UPP1); kinesin family member 18B (KIF18B); kelch-like family member 23 (KLHL23); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); and ubiquitin-like with PHD and ring finger domains 1 (UHRF1).

88. The method of any of claims 11-74, 86, and 87, wherein the one or more first gene set comprises a plurality of genes selected from the group consisting of: MCM3, CENPM, TRIP13, UBE2S, SPC24, CDC25A, RFC3, ASF1B, H2AFX, DDX39A, GINS1, UBE2T, POLD1, TK1, CDK4, RNASEH2A, KIF18B, DNMT1, ESPL1, SNRPB, MCM3, CDC6, UBE2S, CDC25A, H2AFX, DDX39A, CDK4, E2F2, RAD54L, E2F1, ESPL1, MCM2, GINS2, POLQ, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, CDK1, EBP, SLC1A5, CDC25A, DDX39A GLA, STC1, MCM2 RRM2, HSPE1, ACLY, TMEM97, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, CDK4, HSPE1, FARSA, TMEM97, MCM4, UNG, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2.

89. The method of any of claims 11-74, and 86-88, wherein the one or more second gene set comprises a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, (LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, (IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, and LINC00239.

90. The method of any one of claims 11-74 and 86-89, wherein the one or more second gene set comprises a plurality of genes selected from the group consisting of: LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2.

91. The method of any of claims 11-74 and 86-90, wherein the one or more second gene set comprises a plurality of genes selected from the group consisting of: FYN, TXK, ZBP1, TMEM71, and KIAA1551.

92. The method of any of claims 11-74 and 86-91, wherein the one or more second gene set comprises a plurality of genes selected from the group consisting of: KLRB1, CD40LG, ICOS, CD28, and CCL21.

93. The method of any of claims 4-10 and 14-92, wherein the one or more second gene set comprises a plurality of genes selected from the group consisting of: PDCD1, LAG3, and TIGIT.

94. The method of any of claims 11-74 and 86-93, wherein the plurality of genes comprises between about 2 and about 150 genes, between about 10 and about 150 genes, between about 20 and about 150 genes, between about 50 and about 150 genes, between about 100 and about 150 genes, between about 2 and 100 genes, between about 10 and about 100 genes, between about 20 and about 100 genes, between about 50 and about 100 genes, between about 2 and about 50 genes, between about 10 and about 50 genes, between about 20 and about 50 genes, between about 2 and about 20 genes, between about 10 and about 20 genes, between about 2 and about 10 genes.

95. The method of any of claims 11-74 and 86-94, wherein the plurality of genes in a gene set is at or about 5 genes, at or about 10 genes, at or about 20 genes, at or about 50 genes, at or about 100 genes, or at or about 150 genes.

96. The method of any of claims 11-74 and 86-95, wherein gene set expression is determined by a method comprising gene set enrichment analysis (GSEA).
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional applications 62/890,607, filed Aug. 22, 2019, entitled "COMBINATION THERAPY OF A T CELL THERAPY AND AN ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR AND RELATED METHODS," 63/024,502, filed May 13, 2020, entitled "COMBINATION THERAPY OF A T CELL THERAPY AND AN ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR AND RELATED METHODS," and 63/037,584, filed Jun. 10, 2020, entitled "COMBINATION THERAPY OF A T CELL THERAPY AND AN ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR AND RELATED METHODS," the contents of which are incorporated by reference in their entirety for all purposes.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042021440SeqList.TXT, created Aug. 6, 2020, which is 36,864 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

FIELD

[0003] The present disclosure relates in some aspects to methods and uses of combination therapies involving an immunotherapy or a cell therapy, e.g., a T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2), for treating subjects with cancers such as leukemias and lymphomas, and related methods, uses, and articles of manufacture. The T cell therapy includes cells that express recombinant receptors such as chimeric antigen receptors (CARs).

BACKGROUND

[0004] Various strategies are available for immunotherapy and cell therapy for treating cancers, for example, adoptive cell therapies, including those involving the administration of cells expressing chimeric receptors specific for a disease or disorder of interest, such as chimeric antigen receptors (CARs) and/or other recombinant antigen receptors, as well as other adoptive immune cell and adoptive T cell therapies. Subsets of cancers are resistant to or develop resistance to such therapies. Improved methods are therefore needed, for example, to overcome this resistance and increase the efficacy of such methods. Provided are methods and uses that meet such needs.

SUMMARY

[0005] Provided herein are methods involving combination therapies for treating subjects having or suspected of having a cancer, such as a NHL, or a subtype thereof. The methods and other embodiments generally relate to combinations involving administering to the subject a therapy, which is an immunotherapy or a cell therapy, and an inhibitor of an enhancer of zeste homolog 2 (EZH2). In some aspects, the provided methods involve the administration of a T cell therapy such as CAR-expressing T cells comprising an antigen-binding domain that binds to an antigen associated with, expressed by, or present on cells of the cancer.

[0006] Provided herein is a method of treating cancer including administering to a subject having a cancer a cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer; and administering to the subject an inhibitor of enhancer of zeste homology 2 (EZH2).

[0007] Provided herein is a method of treating cancer including administering to a subject having a cancer an inhibitor of enhancer of zeste homolog 2 (EZH2), wherein the subject is a candidate for being administered or has been administered a cell therapy including T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen associated with, expressed by, or present on cells of the cancer.

[0008] Provided herein is a method of treating cancer including administering a cell therapy including T cells expressing a chimeric antigen receptor (CAR) to a subject having a cancer, wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, wherein the subject is administered or is to be administered an inhibitor of enhancer of zeste homolog 2 (EZH2).

[0009] In some embodiments, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at a time between at or about 14 days prior to and at or about 14 days after initiation of administration of the cell therapy. In some embodiments, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 7 days after initiation of administration of the cell therapy. In some embodiments, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 1 day after initiation of administration of the cell therapy. In some embodiments, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, at least one dose of the EZH2 inhibitor in the dosing regimen is administered concurrently with the cell therapy and/or on the same day as the cell therapy.

[0010] In some embodiments, the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject.

[0011] In some embodiments, the cell therapy includes cells that are autologous to the subject. In some embodiments, a biological sample comprising cells autologous to the subject is collected from the subject. In some embodiments, a biological sample comprising cells autologous to the subject is collected from the subject prior to a lymphodepleting therapy. In some embodiments, the biological sample from the subject is or comprises an apheresis product. In some embodiments, the biological sample from the subject is or comprises a leukapheresis product. In some embodiments, the T cells of the cell therapy are derived from the autologous cells of the biological sample. In some embodiments, the subject is administered a lymphodepleting therapy prior to initiation of administration of the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and prior to initiation of administration of the EZH2 inhibitor and/or the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and initiation of administration of the EZH2. In some embodiments, the administration of the cell therapy includes administration of between about 1.times.10.sup.5 total CAR-expressing T cells and about 5.times.10.sup.8 total CAR-expressing T cells; between about about 1.times.10.sup.5 total CAR-expressing T cells and about 2.times.10.sup.8 total CAR-expressing T cells; between about 1.times.10.sup.6 total CAR-expressing T cells and about 1.times.10.sup.8 total CAR-expressing T cells; or between about 1.times.10.sup.6 total CAR-expressing T cells and 5.times.10.sup.7 total CAR-expressing T cells. In some embodiments, the administration of the cell therapy includes administration of between about 1.times.10.sup.5 total CAR-expressing T cells and about 5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the administration of the cell therapy includes administration of between about about 1.times.10.sup.5 total CAR-expressing T cells and about 2.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the administration of the cell therapy includes administration of between about 1.times.10.sup.6 total CAR-expressing T cells and about 1.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the administration of the cell therapy includes administration of between about 1.times.10.sup.6 total CAR-expressing T cells and 5.times.10.sup.7 total CAR-expressing T cells. In some embodiments, the cell therapy is enriched in CD3+, CD4+, CD8+ or CD4+ and CD8+ T cells. In some embodiments, the cell therapy is enriched in CD3+ T cells. In some embodiments, the cell therapy is enriched in CD4+ T cells. In some embodiments, the cell therapy is enriched in CD8+ T cells. In some embodiments, the cell therapy is enriched in CD4+ and CD8+ T cells.

[0012] In some embodiments, the CD4+ and CD8+ T cells of the cell therapy includes a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells and/or of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells, that is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1. In some embodiments, the CD4+ and CD8+ T cells of the cell therapy includes a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells. In some embodiments, the ratio is or is approximately 1:1. In some embodiments, the ratio is between approximately 1:3 and approximately 3:1.

[0013] In some embodiments, the cell therapy is enriched in CD4.sup.+ and CD8.sup.+ T cells, wherein the administration of the cell therapy includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition including or enriched in the CD8.sup.+ T cells and a second composition including or enriched in the CD4.sup.+ T cells.

[0014] In some embodiments, the CD4+ CAR-expressing T cells in the one of the first and second compositions and the CD8+ CAR-expressing T cells in the other of the first and second compositions are present at a defined ratio that is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1; and/or the CD4+ CAR-expressing T cells and the CD8+ CAR-expressing T cells in the first and second compositions are present at a defined ratio, which ratio is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1. In some embodiments, the CD4+ CAR-expressing T cells in the one of the first and second compositions and the CD8+ CAR-expressing T cells in the other of the first and second compositions are present at a defined ratio. In some embodiments, the CD4+ CAR-expressing T cells and the CD8+ CAR-expressing T cells in the first and second compositions are present at a defined ratio. In some embodiments, the ratio is or is approximately 1:1. In some embodiments, the ratio is between approximately 1:3 and approximately 3:1.

[0015] In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.5 to 5.times.10.sup.8 total CAR-expressing T cells, of from or from about 1.times.10.sup.6 to 2.5.times.10.sup.8 total CAR-expressing T cells, of from or from about 5.times.10.sup.6 to 1.times.10.sup.8 total CAR-expressing T cells, of from or from about 1.times.10.sup.7 to 2.5.times.10.sup.8 total CAR-expressing T cells, or of from or from about 5.times.10.sup.7 to 1.times.10.sup.8 total CAR-expressing T cells, each inclusive. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.5 to 5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.6 to 2.5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 5.times.10.sup.6 to 1.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.7 to 2.5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 5.times.10.sup.7 to 1.times.10.sup.8 total CAR-expressing T cells.

[0016] In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.5 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.5 CAR-expressing T cells, at least or at least about 5.times.10.sup.5 CAR-expressing T cells, at least or at least about 1.times.10.sup.6 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.6 CAR-expressing T cells, at least or at least about 5.times.10.sup.6 CAR-expressing T cells, at least or at least about 1.times.10.sup.7 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.7 CAR-expressing T cells, at least or at least about 5.times.10.sup.7 CAR-expressing T cells, at least or at least about 1.times.10.sup.8 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.8 CAR-expressing T cells, or at least or at least about 5.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.8 CAR-expressing T cells.

[0017] In some embodiments, the cell therapy includes administration of at or about 5.times.10.sup.7 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at or about 1.times.10.sup.8 CAR-expressing cells.

[0018] In some embodiments, the CAR includes an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM. In some embodiments, the antigen is a tumor antigen or is expressed on cells of the cancer. In some embodiments, the antigen is selected from among .alpha.v.beta.6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer/testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22R.alpha.), IL-13 receptor alpha 2 (IL-13R.alpha.2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1). In some embodiments, the antigen is selected from among CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30. In some embodiments, the antigen is CD19.

[0019] In some embodiments, the intracellular signaling domain includes an intracellular domain of a CD3-zeta (CD3.zeta.) chain. In some embodiments, the intracellular signaling region further includes a costimulatory signaling region. In some embodiments, the costimulatory signaling region includes a signaling domain of CD28 or 4-1BB. In some embodiments, the costimulatory signaling region includes a signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB. In some embodiments, the costimulatory domain is or includes a signaling domain of CD28. In some embodiments, the costimulatory domain is or includes a signaling domain of 4-1BB. In some embodiments, the costimulatory domain is or includes a signaling domain of human CD28. In some embodiments, the costimulatory domain is or includes a signaling domain of human 4-1BB.

[0020] In some embodiments, the method includes collecting a biological sample from the subject including cells autologous to the subject prior to initiation of administration of the inhibitor. In some embodiments, the biological sample from the subject is or includes a whole blood sample, a buffy coat sample, a peripheral blood mononuclear cells (PBMC) sample, an unfractionated T cell sample, a lymphocyte sample, a white blood cell sample, an apheresis product, or a leukapheresis product. In some embodiments, the biological sample from the subject is or includes an apheresis product. In some embodiments, the biological sample from the subject is or includes a leukapheresis product.

[0021] In some embodiments, the method includes, prior to administration of the cell therapy, administering a lymphodepleting agent or therapy to the subject. In some embodiments, the EZH2 inhibitor is administered to the subject after the lymphodepleting therapy concludes. In some embodiments, the lymphodepleting therapy is completed between 2 and 7 days before the initiation of administration of the cell therapy.

[0022] In some embodiments, the subject is administered a lymphodepleting therapy prior to initiation of administration of the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and prior to initiation of administration of the cell therapy. In some embodiments, the lymphodepleting therapy concludes between 2 and 7 days before initiation of administration of the cell therapy. In some embodiments, the tumor biopsy sample is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the tumor biopsy sample is obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject. In some embodiments, the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy. In some embodiments, administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

[0023] In some embodiments, the lymphodepleting therapy includes the administration of fludarabine and/or cyclophosphamide. In some embodiments, the lymphodepleting therapy includes the administration of fludarabine. In some embodiments, the lymphodepleting therapy includes the administration of cyclophosphamide. In some embodiments, the lymphodepleting therapy includes the administration of fludarabine and cyclophosphamide. In some embodiments, the lymphodepleting therapy comprises administration of cyclophosphamide at about 200-400 mg/m.sup.2, optionally at or about 300 mg/m.sup.2, inclusive, and/or fludarabine at about 20-40 mg/m.sup.2, optionally 30 mg/m.sup.2, daily for 2-4 days, optionally for 3 days, or wherein the lymphodepleting therapy includes administration of cyclophosphamide at about 500 mg/m.sup.2. In some embodiments, the lymphodepleting therapy comprises administration of cyclophosphamide at or about 300 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days; and/or the lymphodepleting therapy includes administration of cyclophosphamide at or about 500 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days.

[0024] In some embodiments, the initiation of administration of the inhibitor is within at or about 5 days prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within at or about 1 day prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is concurrent with or on the same day as initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy, optionally wherein the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy.

[0025] In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor between about 4 weeks prior to initiation of administration of the cell therapy and about 1 week prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 14 days, at or about 7 days, or at or about 1 day prior to and at or about 14 days, at or about 7 days, or at or about 1 day after initiation of administration of the T cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at or about 7 days, at or about 5 days, at or about 3 days, at or about 2 days, or at or about 1 day prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor concurrent with or on the same day as initiation of administration of the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor concurrently with the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor on the same day as the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 7 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 5 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 2 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 1 day before initiation of administration of the cell therapy.

[0026] In some embodiments, the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy. In some embodiments, administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

[0027] In some embodiments, a dose of the inhibitor is an amount of the inhibitor between at or about 100 mg and at or about 1600 mg, between at or about 100 mg and at or about 1200 mg, between at or about 100 mg and at or about 800 mg, between at or about 100 mg and at or about 400 mg, between at or about 100 mg and at or about 200 mg, between at or about 200 mg and at or about 1600 mg, between at or about 200 mg and at or about 1200 mg, between at or about 200 mg and at or about 800 mg, between at or about 200 mg and at or about 400 mg, between at or about 400 mg and at or about 1600 mg, between at or about 400 mg and at or about 1200 mg, between at or about 400 mg and at or about 800 mg, between at or about 800 mg and at or about 1600 mg, between at or about 800 mg and at or about 1200 mg, between at or about 1200 mg and at or about 1600 mg, each inclusive. In some embodiments, a dose is about 200 mg. In some embodiments, a dose is about 400 mg. In some embodiments, a dose is about 800 mg.

[0028] In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 800 mg of the inhibitor per day. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 1600 mg of the inhibitor per day. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 2400 mg of the inhibitor per day.

[0029] In some embodiments, the inhibitor is administered in a dosing regimen that includes two doses each day (twice daily dosing). In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 100 mg and at or about 1600 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 200 mg and at or about 1200 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 400 mg and at or about 800 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 200 mg. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 400 mg. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 800 mg.

[0030] In some embodiments, the inhibitor is administered in a dosing regimen that includes three doses each day (thrice daily dosing). In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 100 mg and at or about 1600 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 200 mg and at or about 1200 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 400 mg and at or about 800 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 200 mg. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 400 mg. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 800 mg.

[0031] In some embodiments, the EZH2 inhibitor is administered for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to five months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to four months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to one month after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered until the subject exhibits a complete response. In some embodiments, the EZH2 inhibitor is administered until the subject exhibits disease progression. In some embodiments, administration of the EZH2 inhibitor is discontinued if the subject exhibits clinical remission.

[0032] In some embodiments, the inhibitor inhibits wild type EZH2 and/or mutant EZH2. In some embodiments, the inhibitor inhibits wild type EZH2. In some embodiments, the inhibitor inhibits mutant EZH2, optionally wherein the mutation is a gain-of-function mutation.

[0033] In some embodiments, EZH2 comprises one or more mutations selected from among Y641C, Y641F, Y641H, Y641N, Y641S, Y646C, Y646F, Y646H, Y646N, Y646S, A677G, A682G, A687V, A692V, K634E, V637A, and V679M. In some embodiments, the mutation increases trimethylation of histone 3 at lysine 27.

[0034] In some embodiments, the inhibitor inhibits EZH2 with a half-maximal inhibitory concentration (IC.sub.50) for wild type and/or mutant EZH2 that is less than or less than about 1000 nM, 900 nM, 800 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 10 nM, or less than or less than about 5 nM. In some embodiments, the half-maximal inhibitory concentration (IC.sub.50) of the inhibitor for EZH2 is lower than the half-maximal inhibitory concentration (IC.sub.50) of the inhibitor for EZH1, optionally at least 2 times lower, at least 5 times lower, 10 times lower, at least 100 times lower, at least 1,000 times lower, at least 5,000 times lower, at least 10,000 times lower, or at least 20,000 times lower.

[0035] In some embodiments, the inhibitor is selected from among the group consisting of tazemetostat (EPZ-6438), CPI-1205, GSK343, GSK126, and valemetostat (DS-3201b). In some embodiments, the inhibitor is tazemetostat (EPZ-6438). In some embodiments, the inhibitor is CPI-1205. In some embodiments, the inhibitor is GSK343. In some embodiments, the inhibitor is GSK126. In some embodiments, the inhibitor is valemetostat (DS-3201b). In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a bladder cancer, a breast cancer, a melanoma, or a prostate cancer. In some embodiments, the solid tumor is a prostate cancer. In some embodiments, the prostate cancer is a castration-resistant prostate cancer (CRPC).

[0036] In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a myeloma, leukemia or lymphoma. In some embodiments, the cancer is an acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), a small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), a large B cell lymphoma.

[0037] In some embodiments, the cancer is a non-Hodgkin lymphoma (NHL). In some embodiments, the NHL is a follicular lymphoma (FL). In some embodiments, the NHL is a diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the DLBCL is not an activated B-cell (ABC) subtype of DLBCL.

[0038] In some embodiments, a subject is selected for treatment with the EZH2 inhibitor as a subject that has a DLBCL. In some embodiments, the subject is selected for treatment with the EZH2 inhibitor as a subject that has a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the subject is selected from treatment with the EZH2 inhibitor as a subject having a pre-treatment tumor biopsy with a DLBCL-like gene expression signature. In some embodiments, the subject is selected from treatment as a subject having a pre-treatment tumor biopsy gene expression signature associated with a progressive disease (PD) response 3 months post-treatment with cell therapy.

[0039] In some embodiments, the method comprises selecting the subject for treatment with the EZH2 inhibitor as a subject that has a DLBCL. In some embodiments, the method comprises selecting the subject for treatment with the EZH2 inhibition as a subject that has a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the method comprises selecting a subject having a pre-treatment tumor biopsy with a DLBCL-like gene expression signature. In some embodiments, the method comprises selecting a subject having a pre-treatment tumor biopsy gene expression signature associated with a progressive disease (PD) response 3 months post-treatment with cell therapy.

[0040] In some embodiments, the subject has relapsed following remission after treatment with, or become refractory to, failed and/or was intolerant to treatment with a prior therapy for treating the cancer. In some embodiments, the cancer is resistant to treatment with the cell therapy alone.

[0041] In some embodiments, the cancer is resistant to treatment with the cell therapy alone. In some embodiments, the cancer exhibits overexpression of EZH2 and/or expression of EZH2 including one or more mutations selected from among Y641C, Y641F, Y641H, Y641N, Y641S, Y646C, Y646F, Y646H, Y646N, Y646S, A677G, A682G, A687V, A692V, K634E, V637A, and V679M, optionally wherein the mutation is a gain-of-function mutation. In some embodiments, the cancer exhibits overexpression of EZH2. In some embodiments, the cancer exhibits one or more mutations in the gene encoding EZH2. In some embodiments, the one or more mutations is a gain-of-function mutation.

[0042] In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice or thrice daily daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice or thrice daily daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice daily or thrice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor, optionally twice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor twice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor thrice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor until the subject exhibits clinical remission. In some embodiments, administration of the inhibitor in the dosing regimen is discontinued if the subject exhibits clinical remission. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor until the subject exhibits disease progression In some embodiments, administration of the inhibitor in the dosing regimen is discontinued if the subject exhibits disease progression.

[0043] In some embodiments, in a plurality of subjects treated, infiltration of the CAR-expressing T cells of the cell therapy into a tumor microenvironment (TME) is increased, compared to a method that does not involve the administration of the inhibitor. In some embodiments, the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject.

[0044] In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E4 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E5 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E2B in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor.

[0045] In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E2 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor.

[0046] In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E3 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E2A in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor.

[0047] In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E4 is upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E5 is upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2B is upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In any of such embodiments, upregulation of the gene set can be determined by gene enrichment analysis methods.

[0048] In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2 is downregulated in the subject, compared expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E3 is downregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2A is downregulated in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In any of such embodiments, downregulation of the gene set can be determined by gene enrichment analysis methods.

[0049] In some embodiments, at least 35%, at least 40% or at least 50% of subjects treated according to the method achieve a complete response (CR) that is durable, or is durable in at least 60, 70, 80, 90, or 95% of subjects achieving the CR, for at or greater than 6 months or at or greater than 9 months; and/or wherein at least 60, 70, 80, 90, or 95% of subjects achieving a CR by six months remain in response, remain in CR, and/or survive or survive without progression, for greater at or greater than 3 months and/or at or greater than 6 months and/or at greater than nine months; and/or at least 50%, at least 60% or at least 70% of the subjects treated according to the method achieve objective response (OR) optionally wherein the OR is durable, or is durable in at least 60, 70, 80, 90, or 95% of subjects achieving the OR, for at or greater than 6 months or at or greater than 9 months; and/or wherein at least 60, 70, 80, 90, or 95% of subjects achieving an OR by six months remain in response or surviving for greater at or greater than 3 months and/or at or greater than 6 months.

[0050] In some embodiments, the tumor biopsy sample is a lymph node biopsy. In some embodiments, the tumor biopsy sample is obtained at a time prior to administering the T cell therapy to the subject, such as within at or about 1 month prior to the subject receiving the T cell therapy. In some embodiments, T cell therapy is autologous to the subject and the tumor biopsy sample is obtained at a time that is at or about at the same time as obtaining (e.g. by apheresis) the T cells from the subject for manufacturing or producing the T cell therapy, e.g. engineered with a recombinant receptor (e.g. CAR). In some embodiments, the tumor biopsy sample is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the tumor biopsy sample is obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

[0051] In some embodiments, the subject is a human.

[0052] Provided herein is a method of treatment with a T cell therapy including (a) assessing (i) the level or amount of one or more first gene selected from EZH2, a gene set forth in Table E2 and/or a gene set forth in Table E2A in a biological sample from a subject and/or (ii) the level or amount of one or more second gene selected from a T cell marker, optionally CD3.epsilon., a gene set forth in Table E4 and/or a gene set forth in Table E2B in a biological sample from the subject, wherein the subject has or is suspected of having a B cell malignancy, and wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; (b) selecting the subject for treatment with a T cell therapy if: (i) the level or amount of the one or more first gene is below a gene reference value; and/or (ii) the level or amount of the one or more second gene is above a gene reference value; and (c) administering to the selected patient a T cell therapy. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0053] Also provided herein is a method of of treating a cancer with a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method including: (a) assessing in a tumor biopsy sample from a subject (i) the level or amount of one or more first gene selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; (b) selecting the subject for treatment with the T cell therapy if: (i) the level or amount of the one or more first gene is below a gene reference value; and/or (ii) the level or amount of the one or more second gene is above a gene reference value; and (c) administering to the selected subject the T cell therapy. In some embodiments, the cancer is a B cell malignancy.

[0054] Also provided herein is a method of treating a cancer with an inhibitor of enhancer of zeste homolog 2 (EZH2) and a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method including: (a) assessing in a tumor biopsy sample from a subject: (i) the level or amount of one or more first gene selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; (b) selecting the subject for treatment if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value; and (c) administering to the selected subject the EZH2 inhibitor and the cell therapy. In some embodiments, the cancer is a B cell malignancy.

[0055] Provided herein is a method of selecting a subject having a cancer for administering an enhancer of zeste homolog 2 (EZH2) inhibitor including (a) assessing (i) the level or amount of one or more first gene selected from EZH2, a gene set forth in Table E2, and/or a gene set forth in Table E2A in a biological sample from the subject and/or (ii) the level or amount of one or more second gene selected from a T cell marker, optionally CD3.epsilon., a gene set forth in Table E4, and/or a gene set forth in Table E2B in a biological sample from the subject, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene, and wherein the subject is to receive administration of a T cell therapy and the biological sample is obtained from the subject prior to the administration of the T cell therapy; and (b) selecting the subject having the cancer for treatment with an EZH2 inhibitor in combination with the T cell therapy if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0056] Also provided herein is a method of selecting a subject having a cancer for administration of an enhancer of zeste homolog 2 (EZH2) inhibitor, the method including (a) assessing (i) the level or amount of one or more first gene in a tumor biopsy sample from the subject selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, HK2, and combinations thereof; and/or (ii) the level or amount of one or more second gene in a biological sample from the subject, selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, IRF2, and combinations thereof, wherein the level or amount of one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene; the subject is to receive administration of a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, and the tumor biopsy sample is obtained from the subject prior to the administration of the cell therapy; and (b) selecting the subject having the cancer for treatment with the EZH2 inhibitor and the cell therapy if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value. In some embodiments, the cancer is a B cell malignancy.

[0057] In some embodiments, the method further includes administering to the selected subject the EZH2 inhibitor in combination with the T cell therapy. In some embodiments, if the subject is not selected for treatment with the EZH2 inhibitor, the method includes administering only the T cell therapy to the subject.

[0058] Provided herein is a method of identifying a subject having a cancer that is predicted to be resistant to treatment with a T cell therapy, the method comprising: (a) assessing (i) the level or amount of one or more first gene selected from EZH2, a gene set forth in Table E2, and/or a gene set forth in Table E2A in a biological sample from the subject and/or (ii) the level or amount of one or more second gene selected from a T cell marker, optionally CD3.epsilon., a gene set forth in Table E4, and/or a gene set forth in Table E2B in a biological sample from the subject, wherein the level or amount of the one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the gene, and wherein the subject is a candidate for administration of a dose of a T cell therapy and the biological sample is obtained from the subject prior to the subject being administered the dose of the T cell therapy; and (b) identifying the subject as having a cancer that is predicted to be resistant to treatment with the T cell therapy if: (i) the level or amount of the one or more first gene is above a gene reference value; and/or (ii) the level or amount of the one or more second gene is below a gene reference value. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0059] Provided herein is a method of determining responsiveness of a subject having a cancer to a T cell therapy including: (a) assessing (i) the level or amount of one or more first gene selected from EZH2, a gene set forth in Table E2, and/or a gene set forth in Table E2A in a biological sample from the subject and/or (ii) the level or amount of one or more second gene selected from a T cell marker, optionally CD3.epsilon., a gene set forth in Table E4, and/or a gene set forth in Table E2B in a biological sample from the subject, wherein the level or amount of the one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene, wherein the biological sample is obtained from the subject at a first time prior to the subject being administered the T cell therapy, and wherein the subject is to receive treatment with the T cell therapy; (b) assessing (i) the level or amount of the one or more first gene in a biological sample from the subject and/or (ii) the level or amount of the one or more second gene in a biological sample from the subject, wherein the level or amount of the one or more gene is the level or amount of a protein and/or a polynucleotide encoded by the one or more gene, wherein the biological sample is obtained from the subject at a second time subsequent to the subject being administered the T cell therapy to the subject, and wherein the subject has been administered the T cell therapy prior to the assessing in (b); and (c) determining that the subject is responsive to the T cell therapy if: (i) the level or amount of the one or more first gene at the second time is lower than the level or amount of the one or more first gene at the first time; and/or (ii) the level or amount of the one or more gene at the second time is higher than the level or amount of the one or more gene at the first time. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0060] In some embodiments, the one or more first genes is EZH2.

[0061] In some embodiments, the one or more second gene includes a T cell marker and the T cell marker is one or more of CD3.epsilon., PDCD1, LAG3, and TIGIT. In some embodiments, at least one of the or more second gene is PDCD1, LAG3, and TIGIT. In some embodiments, at least one of the or more second gene is CD3.epsilon..

[0062] In some embodiments, the one or more first genes is selected from a gene set forth in Table E2. In some embodiments, the one or more first genes is selected from the group consisting of: E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, and UHRF1.

[0063] In some embodiments, the one or more first genes is selected from a gene set forth in Table E2A. In some embodiments, the one or more first genes is selected from the group consisting of: MCM3, CENPM, TRIP13, UBE2S, SPC24, CDC25A, RFC3, ASF1B, H2AFX, DDX39A, GINS1, UBE2T, POLD1, TK1, CDK4, RNASEH2A, KIF18B, DNMT1, ESPL1, SNRPB, MCM3, CDC6, UBE2S, CDC25A, H2AFX, DDX39A, CDK4, E2F2, RAD54L, E2F1, ESPL1, MCM2, GINS2, POLQ, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, CDK1, EBP, SLC1A5, CDC25A, DDX39A GLA, STC1, MCM2 RRM2, HSPE1, ACLY, TMEM97, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, CDK4, HSPE1, FARSA, TMEM97, MCM4, UNG, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2

[0064] In some embodiments, the one or more first gene is set forth in Table E3. In some embodiments, the one or more first gene is selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); minichromosome maintenance complex component 2 (MCM2); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); flap structure-specific endonuclease 1 (FEN1); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); kinesin family member 18B (KIF18B); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); and ubiquitin-like with PHD and ring finger domains 1 (UHRF1).

[0065] In some embodiments, the one or more second genes is a T cell marker. In some embodiments, the one or more second gene includes a T cell marker and the T cell marker is one or more of CD3.epsilon., PDCD1, LAG3, and TIGIT. In some embodiments, at least one of the or more second gene is PDCD1, LAG3, and TIGIT. In some embodiments, at least one of the or more second gene is CD3.epsilon..

[0066] In some embodiments, the one or more second genes is selected from a gene set forth in Table E4. In some embodiments, the one or more second genes is selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, and LINC00239.

[0067] In some embodiments, the one or more second genes is selected from a gene set forth in Table E2B. In some embodiments, the one or more second genes is selected from the group consisting of: LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2.

[0068] In some embodiments, the one or more second gene is set forth in Table E5. In some embodiments, the one or more second gene is selected from the group consisting of: FYN oncogene related to SRC, FGR, YES (FYN); TXK tyrosine kinase (TXK); Z-DNA binding protein 1 (ZBP1); transmembrane protein 71 (TMEM71); and KIAA1551 (KIAA1551).

[0069] In some embodiments, the one or more second gene is selected from the group consisting of PDCD1, LAG3, and TIGIT. In some embodiments, the one or more second gene is selected from the group consisting of KLRB1, CD40LG, ICOS, CD28, and CCL21.

[0070] In some embodiments, the gene reference value is within 25%, within 20%, within 15%, within 10%, or within 5% of an average level or amount of the one or more gene in (a) a population of subjects not having the cancer or B cell malignancy or (b) a population of subjects having the cancer or B cell malignancy and administered the therapy, who went on to exhibit a partial response (PR) or complete response (CR) following administration of the therapy. In some embodiments, the population of subjects having the cancer or B cell malignancy went on to exhibit PR or CR at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or more following administration of the therapy.

[0071] In some embodiments, the level or amount of the first one or more genes and/or the second one or more genes is assessed in the biological sample that is obtained before a lymphodepleting therapy is administered to the subject, optionally within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject. In some embodiments, the level or amount of the first one or more genes and/or the second one or more genes is assessed in a tumor biopsy sample that is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the level of amount of the first one or more genes and/or the second one or more genes is assed in a tumor biopsy sample obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

[0072] Provided herein in a method of treating a cancer with a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method including: (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from a subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATPSG1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2; (b) selecting the subject for treatment with the cell therapy if: (i) the expression of the one or more first gene set is downregulated; and/or (ii) the expression of the one or more second gene set is upregulated; and (c) administering to the selected patient the T cell therapy. In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0073] Also provided herein is a method of treating a cancer with an inhibitor of enhancer of zeste homolog 2 (EZH2) and a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, the method including: (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from a subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2; (b) selecting the subject for treatment with the EZH2 inhibitor and the cell therapy if: (i) the expression of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated; and (c) administering to the selected patient the EZH2 inhibitor and the T cell therapy. In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0074] Provided herein is a method of treatment with a T cell therapy, including (a) assessing (i) the expression of one or more first gene set given by Table E2 and/or Table E2A in a biological sample from a subject and/or (ii) the expression of one or more second gene set given by Table E4 and/or Table E2B in a biological sample from the subject, wherein the subject has or is suspected of having a B cell malignancy; (b) selecting the subject for treatment with a T cell therapy if: (i) the expression of the one or more first gene set is downregulated; and/or (ii) the expression of the one or more second gene set is upregulated; and (c) administering to the selected patient a T cell therapy. In some embodiments, upregulation of the first gene set is determined by gene enrichment analysis methods. In some embodiments, downregulation of the second gene set is determined by gene enrichment analysis methods. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0075] Provided herein is a method of selecting a subject having a cancer for administering an enhancer of zeste homolog 2 (EZH2) inhibitor, including (a) assessing (i) the expression of one or more first gene set given by Table E2 and/or Table E2A in a biological sample from the subject and/or (ii) the expression of one or more second gene set given by Table E4 and/or Table E2B in a biological sample from the subject, wherein the subject is to receive administration of a T cell therapy and the biological sample is obtained from the subject prior to the administration of the T cell therapy; and (b) selecting the subject having the cancer for treatment with an EZH2 inhibitor in combination with the T cell therapy if: (i) the level or amount of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated. In some embodiments, upregulation of the first gene set is determined by gene enrichment analysis methods. In some embodiments, downregulation of the second gene set is determined by gene enrichment analysis methods. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0076] Provided herein is a method of identifying a subject having a cancer that is predicted to be resistant to treatment with a T cell therapy, the method including (a) assessing (i) the expression of one or more first gene set given by Table E2 and/or Table E2A in a biological sample from the subject and/or (ii) the expression of one or more second gene set given by Table E4 and/or Table E2B in a biological sample from the subject, wherein the subject is a candidate for administration of a dose of a T cell therapy and the biological sample is obtained from the subject prior to the subject being administered the dose of the T cell therapy; and (b) identifying the subject as having a cancer that is predicted to be resistant to treatment with the T cell therapy if: (i) the expression of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated. In some embodiments, upregulation of the first gene set is determined by gene enrichment analysis methods. In some embodiments, downregulation of the second gene set is determined by gene enrichment analysis methods. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0077] Provided herein is a method of selecting a subject having a cancer for administration an enhancer of zeste homolog 2 (EZH2) inhibitor, the method including (a) assessing (i) the expression of one or more first gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: EZH2, E2F2, RAD51, POLQ, POLD1, MCM10, TRIP13, TFRC, MCM2, ENO1, GTSE1, UBE2T, CAD, ORC1, TPX2, ICAM1, KIF4A, CDC6, CENPM, POLE2, MTHFD1, GINS1, MYBL2, E2F1, FAM83D, CENPI, OIP5, RNASEH2A, ASF1B, CCNE1, SLC1A5, MRPL4, NAMPT, NPM3, TMEM97, NCAPG, CDCA3, MCM3, GMNN, VEGFA, SLC29A1, KIF20A, CENPA, CDC20, DUSP1, CDK2, XPO5, PAICS, E2F8, TUBG1, TOP2A, PCNA, RFC3, CCNB1, SLC43A3, TROAP, ESPL1, TCF19, SLC39A8, DIAPH3, KIF2C, NUF2, DTL, CDCA5, NCAPG2, GINS4, PLIN2, MKI67, CENPU, SKA1, MAPK13, TAGLN2, FDPS, RECQL4, ATF3, IER5, TKT, CDC25A, E2F7, RRM1, CDT1, SLC3A2, FEN1, ATF5, FASN, CDK1, POLH, RRM2, TYMS, GSG2, JUN, AURKB, GINS3, UPP1, KIF18B, KLHL23, KIFC1, NME1, UHRF1, UBE2S, SPC24, H2AFX, DDX39A, TK1, CDK4, DNMT1, SNRPB, RAD54L, GINS2, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, EBP, GLA, STC1, HSPE1, ACLY, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, FARSA, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2; and/or (ii) the expression of one or more second gene set in a tumor biopsy sample from the subject, each gene set comprising a plurality of genes selected from the group consisting of: CACNA2D2, AASS, TENM1, TRAF3IP3, FYN, CD6, PRKCH, ARAP2, PRKCQ, IPCEF1, TXK, ARHGAP15, TNRC6C, TCF7, CETP, SIRPG, RNF125, CD40LG, RRN3P2, OLFM2, GATA3, CUBN, SPOCK2, INPP4B, CD5, ST8SIA1, C7, ITK, LIFR, PLCL1, CD2, CCND2, CLU, ZBP1, BCL11B, CHN1, CATSPERB, IL6ST, CCL21, PLCB2, STAT4, KLRG1, SLC12A6, FBLN7, SCML4, SLC22A3, GPR174, TTC12, PLCH2, CCDC102B, CYSLTR2, NMT2, CD8A, ANKRD29, TTC39B, ADAMTS3, SV2A, UBASH3A, VCAM1, TGFBR2, TRAT1, CTLA4, ICOS, CD200R1, PTPN13, DNASE1L3, F2RL2, ACSL6, SAMD3, KCNK5, TMEM71, TC2N, SLFN5, EVA1C, SGSM1, CD3D, ABCA3, GPR183, ANKK1, OR2A20P, S1PR1, ZNF483, XCR1, CCD7, KIAA1551, GCNT4, KCNA2, CD28, GIMAP7, ANKRD18A, TIGIT, CCR4, SH2D1A, IL3RA, GPRIN3, EVI2B, NAP1L2, SELL, DTHD1, CLEC4C, ALPK2, CD3E, L3MBTL3, ARRDC5, LAT, PATL2, A2M-AS1, LINC01550, GVINP1, LINC00239, PDCD1, LAG3, KLRB1, LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2, wherein the subject is to receive administration of a T cell therapy including T cells expressing a chimeric antigen receptor (CAR), wherein the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the cancer, and the tumor biopsy sample is obtained from the subject prior to the administration of the cell therapy; and (b) selecting the subject having the cancer for treatment with the EZH2 inhibitor and the cell therapy if: (i) the level or amount of the one or more first gene set is upregulated; and/or (ii) the expression of the one or more second gene set is downregulated. In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0078] In some embodiments, provided herein is a method of determining responsiveness of a subject having a cancer to a T cell therapy, including (a) assessing (i) the expression of one or more first gene set given by Table E2 and/or Table E2A in a biological sample from the subject and/or (ii) the expression of one or more second gene set given by Table E4 and/or Table E2B in a biological sample from the subject, wherein the biological sample is obtained from the subject at a first time prior to the subject being administered the T cell therapy, and wherein the subject is to receive treatment with the T cell therapy; (b) assessing (i) the expression of the one or more first gene set in a biological sample from the subject and/or (ii) the expression of the one or more second gene set in a biological sample from the subject, wherein the biological sample is obtained from the subject at a second time subsequent to the subject being administered the T cell therapy to the subject, and wherein the subject has been administered the T cell therapy prior to the assessing in (b); and (c) determining that the subject is responsive to the T cell therapy if: (i) the expression of the one or more first gene set at the second time is less upregulated or more downregulated compared to expression of the one or more first gene set at the first time; and/or (ii) the expression of the one or more second gene set at the second time is more upregulated or less downregulated compared to the one or more second gene set at the first time. In some embodiments, downregulation of the first gene set is determined by gene enrichment analysis methods. In some embodiments, upregulation of the second gene set is determined by gene enrichment analysis methods. In some embodiments, the T cell therapy incudes T cells expressing a chimeric antigen receptor (CAR). In some embodiments, the method of treating is for treating a cancer that is a B cell malignancy and the CAR specifically binds to an antigen associated with, expressed by, or present on cells of the B cell malignancy.

[0079] In some embodiments, the method further includes, prior to the assessing in (b), administering to the subject the T cell therapy.

[0080] In some embodiments, the one or more first gene set is given by Table E3. In some embodiments, the one or more first gene set comprises a plurality of genes selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); minichromosome maintenance complex component 2 (MCM2); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (0IP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); flap structure-specific endonuclease 1 (FEN1); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); kinesin family member 18B (KIF18B); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); and ubiquitin-like with PHD and ring finger domains 1 (UHRF1).

[0081] In some embodiments the one or more first gene set comprises a plurality of genes selected from the group consisting of: E2F transcription factor 2 (E2F2); RAD51 recombinase (RAD51); polymerase (DNA directed), theta (POLQ); polymerase (DNA directed), delta 1, catalytic subunit (POLD1); minichromosome maintenance complex component 10 (MCM10); thyroid hormone receptor interactor 13 (TRIP13); transferrin receptor (TFRC); minichromosome maintenance complex component 2 (MCM2); enolase 1, (alpha) (ENO1); G-2 and S-phase expressed 1 (GTSE1); ubiquitin-conjugating enzyme E2T (putative) (UBE2T); carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD); origin recognition complex, subunit 1 (ORC1); TPX2, microtubule-associated (TPX2); intercellular adhesion molecule 1 (ICAM1); kinesin family member 4A (KIF4A); cell division cycle 6 (CDC6); centromere protein M (CENPM); polymerase (DNA directed), epsilon 2, accessory subunit (POLE2); methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase (MTHFD1); GINS complex subunit 1 (Psf1 homolog) (GINS1); v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2); E2F transcription factor 1 (E2F1); family with sequence similarity 83, member D (FAM83D); centromere protein I (CENPI); Opa interacting protein 5 (OIP5); ribonuclease H2, subunit A (RNASEH2A); anti-silencing function 1B histone chaperone (ASF1B); cyclin E1 (CCNE1); solute carrier family 1 (neutral amino acid transporter), member 5 (SLC1A5); mitochondrial ribosomal protein L4 (MRPL4); nicotinamide phosphoribosyltransferase (NAMPT); nucleophosmin/nucleoplasmin 3 (NPM3); transmembrane protein 97 (TMEM97); non-SMC condensin I complex, subunit G (NCAPG); cell division cycle associated 3 (CDCA3); minichromosome maintenance complex component 3 (MCM3); geminin, DNA replication inhibitor (GMNN); vascular endothelial growth factor A (VEGFA); solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1); kinesin family member 20A (KIF20A); centromere protein A (CENPA); cell division cycle 20 (CDC20); dual specificity phosphatase 1 (DUSP1); cyclin-dependent kinase 2 (CDK2); exportin 5 (XPO5); phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS); E2F transcription factor 8 (E2F8); tubulin, gamma 1 (TUBG1); topoisomerase (DNA) II alpha 170 kDa (TOP2A); proliferating cell nuclear antigen (PCNA); replication factor C (activator 1) 3, 38 kDa (RFC3); cyclin B1 (CCNB1); solute carrier family 43, member 3 (SLC43A3); trophinin associated protein (TROAP); extra spindle pole bodies homolog 1 (S. cerevisiae) (ESPL1); transcription factor 19 (TCF19); solute carrier family 39 (zinc transporter), member 8 (SLC39A8); diaphanous-related formin 3 (DIAPH3); kinesin family member 2C (KIF2C); NUF2, NDC80 kinetochore complex component (NUF2); denticleless E3 ubiquitin protein ligase homolog (Drosophila) (DTL); cell division cycle associated 5 (CDCA5); non-SMC condensin II complex, subunit G2 (NCAPG2); GINS complex subunit 4 (Sld5 homolog) (GINS4); perilipin 2 (PLIN2); marker of proliferation Ki-67 (MKI67); centromere protein U (CENPU); spindle and kinetochore associated complex subunit 1 (SKA1); mitogen-activated protein kinase 13 (MAPK13); transgelin 2 (TAGLN2); farnesyl diphosphate synthase (FDPS); RecQ protein-like 4 (RECQL4); activating transcription factor 3 (ATF3); immediate early response 5 (IER5); transketolase (TKT); cell division cycle 25A (CDC25A); E2F transcription factor 7 (E2F7); ribonucleotide reductase M1 (RRM1); chromatin licensing and DNA replication factor 1 (CDT1); solute carrier family 3 (amino acid transporter heavy chain), member 2 (SLC3A2); flap structure-specific endonuclease 1 (FEN1); activating transcription factor 5 (ATFS); fatty acid synthase (FASN); cyclin-dependent kinase 1 (CDK1); polymerase (DNA directed), eta (POLH); ribonucleotide reductase M2 (RRM2); thymidylate synthetase (TYMS); germ cell associated 2 (haspin) (GSG2); jun proto-oncogene (JUN); aurora kinase B (AURKB); GINS complex subunit 3 (Psf3 homolog) (GINS3); uridine phosphorylase 1 (UPP1); kinesin family member 18B (KIF18B); kelch-like family member 23 (KLHL23); kinesin family member C1 (KIFC1); NME/NM23 nucleoside diphosphate kinase 1 (NME1); and ubiquitin-like with PHD and ring finger domains 1 (UHRF1).

[0082] In some embodiments, the one or more first gene set comprises a plurality of genes selected from the group consisting of: MCM3, CENPM, TRIP13, UBE2S, SPC24, CDC25A, RFC3, ASF1B, H2AFX, DDX39A, GINS1, UBE2T, POLD1, TK1, CDK4, RNASEH2A, KIF18B, DNMT1, ESPL1, SNRPB, MCM3, CDC6, UBE2S, CDC25A, H2AFX, DDX39A, CDK4, E2F2, RAD54L, E2F1, ESPL1, MCM2, GINS2, POLQ, CDKN2C, RACGAP1, SLC7A1, CHAF1A, MT2A, CDK1, EBP, SLC1A5, CDC25A, DDX39A GLA, STC1, MCM2 RRM2, HSPE1, ACLY, TMEM97, MCM4, UNG, DHCR24, HSPA9, INSIG1, ATP5G1, SLC37A4, CANX, CACYBP, BYSL, PHB, CDK4, HSPE1, FARSA, TMEM97, MCM4, UNG, NOP56, PA2G4, SORD, EXOSC5, TBRG4, TCOF1, MRTO4, SRM, RRP12, HSPD1, NOP16, and HK2.

[0083] In some embodiments, the one or more second gene set comprises a plurality of genes selected from the group consisting of: calcium channel, voltage-dependent, alpha 2/delta subunit 2 (CACNA2D2); aminoadipate-semialdehyde synthase (AASS); teneurin transmembrane protein 1 (TENM1); TRAF3 interacting protein 3 (TRAF3IP3); FYN oncogene related to SRC, FGR, YES (FYN); CD6 molecule (CD6); protein kinase C, eta (PRKCH); ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 2 (ARAP2); protein kinase C, theta (PRKCQ); interaction protein for cytohesin exchange factors 1 (IPCEF1); TXK tyrosine kinase (TXK); Rho GTPase activating protein 15 (ARHGAP15); trinucleotide repeat containing 6C (TNRC6C); transcription factor 7 (T-cell specific, HMG-box) (TCF7); cholesteryl ester transfer protein, plasma (CETP); signal-regulatory protein gamma (SIRPG); ring finger protein 125, E3 ubiquitin protein ligase (RNF125); CD40 ligand (CD40LG); RNA polymerase I transcription factor homolog (S. cerevisiae) pseudogene 2 (RRN3P2); olfactomedin 2 (OLFM2); GATA binding protein 3 (GATA3); cubilin (intrinsic factor-cobalamin receptor) (CUBN); sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2 (SPOCK2); inositol polyphosphate-4-phosphatase, type II, 105 kDa (INPP4B); CD5 molecule (CD5); ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (ST8SIA1); complement component 7 (C7); IL2-inducible T-cell kinase (ITK); leukemia inhibitory factor receptor alpha (LIFR); phospholipase C-like 1 (PLCL1); CD2 molecule (CD2); cyclin D2 (CCND2); clusterin (CLU); Z-DNA binding protein 1 (ZBP1); B-cell CLL/lymphoma 11B (zinc finger protein) (BCL11B); chimerin 1 (CHN1); catsper channel auxiliary subunit beta (CATSPERB); interleukin 6 signal transducer (gp130, oncostatin M receptor) (IL6ST); chemokine (C-C motif) ligand 21 (CCL21); phospholipase C, beta 2 (PLCB2); signal transducer and activator of transcription 4 (STAT4); killer cell lectin-like receptor subfamily G, member 1 (KLRG1); solute carrier family 12 (potassium/chloride transporter), member 6 (SLC12A6); fibulin 7 (FBLN7); sex comb on midleg-like 4 (Drosophila) (SCML4); solute carrier family 22 (organic cation transporter), member 3 (SLC22A3); G protein-coupled receptor 174 (GPR174); tetratricopeptide repeat domain 12 (TTC12); phospholipase C, eta 2 (PLCH2); coiled-coil domain containing 102B (CCDC102B); cysteinyl leukotriene receptor 2 (CYSLTR2); N-myristoyltransferase 2 (NMT2); CD8a molecule (CD8A); ankyrin repeat domain 29 (ANKRD29); tetratricopeptide repeat domain 39B (TTC39B); ADAM metallopeptidase with thrombospondin type 1 motif, 3 (ADAMTS3); synaptic vesicle glycoprotein 2A (SV2A); ubiquitin associated and SH3 domain containing A (UBASH3A); vascular cell adhesion molecule 1 (VCAM1); transforming growth factor, beta receptor II (70/80 kDa) (TGFBR2); T cell receptor associated transmembrane adaptor 1 (TRAT1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4); inducible T-cell co-stimulator (ICOS); CD200 receptor 1 (CD200R1); protein tyrosine phosphatase, non-receptor type 13 (APO-1/CD95 (Fas)-associated phosphatase) (PTPN13); deoxyribonuclease I-like 3 (DNASE1L3); coagulation factor II (thrombin) receptor-like 2 (F2RL2); acyl-CoA synthetase long-chain family member 6 (ACSL6); sterile alpha motif domain containing 3 (SAMD3); potassium channel, subfamily K, member 5 (KCNK5); transmembrane protein 71 (TMEM71); tandem C2 domains, nuclear (TC2N); schlafen family member 5 (SLFN5); eva-1 homolog C (C. elegans) (EVA1C); small G protein signaling modulator 1 (SGSM1); CD3d molecule, delta (CD3-TCR complex) (CD3D); ATP-binding cassette, sub-family A (ABC1), member 3 (ABCA3); G protein-coupled receptor 183 (GPR183); ankyrin repeat and kinase domain containing 1 (ANKK1); olfactory receptor, family 2, subfamily A, member 20 pseudogene (OR2A20P); sphingosine-1-phosphate receptor 1 (S1PR1); zinc finger protein 483 (ZNF483); chemokine (C motif) receptor 1 (XCR1); CD7 molecule (CD7); KIAA1551 (KIAA1551); glucosaminyl (N-acetyl) transferase 4, core 2 (GCNT4); potassium voltage-gated channel, shaker-related subfamily, member 2 (KCNA2); CD28 molecule (CD28); GTPase, IMAP family member 7 (GIMAP7); ankyrin repeat domain 18A (ANKRD18A); T cell immunoreceptor with Ig and ITIM domains (TIGIT); chemokine (C-C motif) receptor 4 (CCR4); SH2 domain containing 1A (SH2D1A); interleukin 3 receptor, alpha (low affinity) (IL3RA); GPRIN family member 3 (GPRIN3); ecotropic viral integration site 2B (EVI2B); nucleosome assembly protein 1-like 2 (NAP1L2); selectin L (SELL); death domain containing 1 (DTHD1); C-type lectin domain family 4, member C (CLEC4C); alpha-kinase 2 (ALPK2); CD3e molecule, epsilon (CD3-TCR complex) (CD3.epsilon.); l(3)mbt-like 3 (Drosophila) (L3MBTL3); arrestin domain containing 5 (ARRDC5); linker for activation of T cells (LAT); protein associated with topoisomerase II homolog 2 (yeast) (PATL2); A2M antisense RNA 1 (A2M-AS1); LINC01550 (LINC01550); GTPase, very large interferon inducible pseudogene 1 (GVINP1); and long intergenic non-protein coding RNA 239 (LINC00239).

[0084] In some embodiments, the one or more second gene set comprises a plurality of genes selected from the group consisting of: LAP3, LGALS3BP, ADAR, ELF1, TRIM14, USP18, TDRD7, PROCR, TMEM140, IFI35, TRIM25, TRIM5, CXCL10, PARP12, C1S, NCOA7, GBP2, UBA7, IFI44L, and IRF2.

[0085] In some embodiments, the one or more second gene set is given by Table E5. In some embodiments, the one or more second gene set comprises a plurality of genes selected from the group consisting of: FYN oncogene related to SRC, FGR, YES (FYN); TXK tyrosine kinase (TXK); Z-DNA binding protein 1 (ZBP1); transmembrane protein 71 (TMEM71); and KIAA1551 (KIAA1551).

[0086] In some embodiments, the one or more second gene set comprises a plurality of genes selected from the group consisting of: KLRB1, CD40LG, ICOS, CD28, and CCL21. In some embodiments, the one or more second gene set comprises a plurality of genes selected from the group consisting of: PDCD1, LAG3, and TIGIT.

[0087] In some embodiments, the plurality of genes comprises at least 2 genes, at least 5 genes, at least 10 genes, at least 20 genes, at least 30 genes, at least 40 genes, at least 50 genes, at least 60 genes, at least 70 genes, at least 80 genes, at least 90 genes, at least 100 genes, or at least 150 genes. In some embodiments, the plurality of genes comprises at least 2 genes. In some embodiments, the plurality of genes comprises at least 5 genes. In some embodiments, the plurality of genes comprises at least 10 genes. In some embodiments, the plurality of genes comprises at least 20 genes. In some embodiments, the plurality of genes comprises at least 30 genes. In some embodiments, the plurality of genes comprises at least 40 genes. In some embodiments, the plurality of genes comprises at least 50 genes. In some embodiments, the plurality of genes comprises at least 60 genes. In some embodiments, the plurality of genes comprises at least 70 genes. In some embodiments, the plurality of genes comprises at least 80 genes. In some embodiments, the plurality of genes comprises at least 90 genes. In some embodiments, the plurality of genes comprises at least 100 genes. In some embodiments, the plurality of genes comprises at least 150 genes.

[0088] In some embodiments, the plurality of genes comprises between about 2 and about 150 genes, between about 10 and about 150 genes, between about 20 and about 150 genes, between about 50 and about 150 genes, between about 100 and about 150 genes, between about 2 and 100 genes, between about 10 and about 100 genes, between about 20 and about 100 genes, between about 50 and about 100 genes, between about 2 and about 50 genes, between about 10 and about 50 genes, between about 20 and about 50 genes, between about 2 and about 20 genes, between about 10 and about 20 genes, between about 2 and about 10 genes. In some embodiments, the plurality of genes comprises between about 2 genes and about 150 genes. In some embodiments, the plurality of genes comprises between about 10 genes and about 100 genes. In some embodiments, the plurality of genes comprises between about 20 genes and about 50 genes. In some embodiments, the plurality of genes in a gene set is at or about 5 genes. In some embodiments, the plurality of genes in a gene set is at or about 10 genes. In some embodiments, the plurality of genes in a gene set is at or about 20 genes. In some embodiments, the plurality of genes in a gene set is at or about 50 genes. In some embodiments, the plurality of genes in a gene set is at or about 100 genes. In some embodiments, the plurality of genes in a gene set is at or about 150 genes.

[0089] In some embodiments, gene set expression is determined by a method comprising gene set enrichment analysis (GSEA).

[0090] In some embodiments, if the subject is identified as having a cancer that is predicted to be resistant to treatment with the T cell therapy, the method further includes administering an alternative treatment to the identified subject, wherein the alternative treatment is selected from among the following: a combination treatment including the T cell therapy and an additional agent that modulates or increases the activity of the T cell therapy; an increased dose of the T cell therapy; and/or a chemotherapeutic agent.

[0091] In some embodiments, the alternative treatment is a combination treatment including the T cell therapy and an additional agent that modulates or increases the activity of the T cell therapy, optionally wherein the additional agent is an immune checkpoint inhibitor, a modulator of a metabolic pathway, an adenosine receptor antagonist, a kinase inhibitor, an anti-TGF.beta. antibody or an anti-TGF.beta.R antibody, a cytokine, and/or an EZH2 inhibitor. In some embodiments, the alternative treatment is a combination treatment including the T cell therapy and an EZH2 inhibitor. In some embodiments, the alternative treatment is an increased dose of the T cell therapy compared to a dose of the T cell therapy given to a subject not identified as having a cancer that is predicted to be resistant to treatment with the T cell therapy, optionally wherein T cell therapy includes cells expressing a recombinant receptor that binds to an antigen associated with, expressed by, or present on the cells of the cancer.

[0092] In some embodiments, the increased dose of the T cell therapy includes an increased number of cells of the T cell therapy, as compared to the dose of the T cell therapy given to a subject not identified as having a cancer that is predicted to be resistant to treatment with the T cell therapy.

[0093] In some embodiments, the alternative treatment is a chemotherapeutic agent, optionally wherein the chemotherapeutic agent is cyclophosphamide, doxorubicin, prednisone, vincristine, fludarabine, bendamustine, and/or rituximab.

[0094] In some embodiments, if the subject is not identified as having a cancer that is predicted to be resistant to treatment with the T cell therapy, the method includes administering only the dose of the T cell therapy to the subject. In some embodiments, the method further includes administering to the identified subject an EZH2 inhibitor.

[0095] In some embodiments, the expression of the one or more first gene set and/or the one or more second gene set is assessed in the biological sample that is obtained before a lymphodepleting therapy is administered to the subject, optionally within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject. In some embodiments, the expression of the one or more first gene set and/or the one or more second gene set is assessed in a tumor biopsy sample that is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the expression of the one or more first gene set and/or the one or more second gene set is assessed in a tumor biopsy sample obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

[0096] In some embodiments, the biological sample is obtained from the subject at a time before a lymphodepleting therapy is administered to the subject, optionally within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject. In some embodiments, the biological sample is obtained from the subject at a time before a lymphodepleting therapy is administered to the subject. In some embodiments, the biological sample is obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

[0097] In some embodiments, the cell therapy comprises cells that are autologous to the subject. In some embodiments, a biological sample comprising cells autologous to the subject is collected from the subject. In some embodiments, a biological sample comprising cells autologous to the subject is collected from the subject prior to a lymphodepleting therapy. In some embodiments, the biological sample from the subject is or comprises an apheresis product. In some embodiments, the biological sample from the subject is or comprises a leukapheresis product. In some embodiments, the T cells of the cell therapy are derived from the autologous cells of the biological sample. In some embodiments, the subject is administered a lymphodepleting therapy prior to initiation of administration of the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and prior to initiation of administration of the EZH2 inhibitor and/or the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and initiation of administration of the EZH2.

[0098] In some embodiments, if a subject is administered both a T cell therapy and an EZH2 inhibitor, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at a time between at or about 14 days, at or about 7 days, or at or about 1 day prior to and at or about 14 days, at or about 7 days, or at or about 1 day after initiation of administration of the T cell therapy.

[0099] In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy, optionally wherein the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy.

[0100] In some embodiments, the dosing regimen of the EZH2 inhibitor includes initiation of administration of the inhibitor at at or about 7 days, at or about 5 days, at or about 3 days, at or about 2 days, or at or about 1 day prior to initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor is concurrent with or on the same day as initiation of administration of the cell therapy.

[0101] In some embodiments, at least one dose of the EZH2 inhibitor in the dosing regimen is administered concurrently with the cell therapy and/or on the same day as the T cell therapy. In some embodiments, at least one dose of the EZH2 inhibitor in the dosing regimen is administered concurrently with the cell therapy. In some embodiments, at least one dose of the EZH2 inhibitor in the dosing regimen is administered on the same day as the T cell therapy.

[0102] In In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor between about 4 weeks prior to initiation of administration of the cell therapy and about 1 week prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 14 days, at or about 7 days, or at or about 1 day prior to and at or about 14 days, at or about 7 days, or at or about 1 day after initiation of administration of the T cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at or about 7 days, at or about 5 days, at or about 3 days, at or about 2 days, or at or about 1 day prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor concurrent with or on the same day as initiation of administration of the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor concurrently with the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor on the same day as the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 7 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 5 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 2 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 1 day before initiation of administration of the cell therapy.

[0103] In some embodiments, the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy. In some embodiments, administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

[0104] In some embodiments, the T cell therapy includes cells that are autologous to the subject. In some embodiments, the T cell therapy is selected from among the group consisting of a tumor infiltrating lymphocytic (TIL) therapy, an endogenous T cell therapy, a transgenic T cell receptor (TCR) therapy, a T cell-engaging therapy, which optionally is a bispecific T cell-engaging therapy (BiTE), and a recombinant receptor-expressing cell therapy, which optionally is a chimeric antigen receptor (CAR)-expressing cell therapy. In some embodiments, the T cell therapy includes a dose of cells expressing a recombinant receptor that specifically binds to an antigen associated with, expressed by, or present on cells of the cancer or B cell malignancy. In some embodiments, the T cell therapy includes T cells expressing a chimeric antigen receptor (CAR).

[0105] In some embodiments, administration of the T cell therapy comprises administration of between about 1.times.10.sup.5 total CAR-expressing T cells and about 5.times.10.sup.8 total CAR-expressing T cells; between about about 1.times.10.sup.5 total CAR-expressing T cells and about 2.times.10.sup.8 total CAR-expressing T cells; between about 1.times.10.sup.6 total CAR-expressing T cells and about 1.times.10.sup.8 total CAR-expressing T cells; or between about 1.times.10.sup.6 total CAR-expressing T cells and 5.times.10.sup.7 total CAR-expressing T cells. In some embodiments, administration of the T cell therapy comprises administration of between about 1.times.10.sup.5 total CAR-expressing T cells and about 5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, administration of the T cell therapy comprises administration of between about about 1.times.10.sup.5 total CAR-expressing T cells and about 2.times.10.sup.8 total CAR-expressing T cells. In some embodiments, administration of the T cell therapy comprises administration of between about 1.times.10.sup.6 total CAR-expressing T cells and about 1.times.10.sup.8 total CAR-expressing T cells. In some embodiments, administration of the T cell therapy comprises administration of between about 1.times.10.sup.6 total CAR-expressing T cells and 5.times.10.sup.7 total CAR-expressing T cells.

[0106] In some embodiments, the T cell therapy is enriched in CD3+, CD4+, CD8+ or CD4+ and CD8+ T cells. In some embodiments, the cell therapy is enriched in CD3+ T cells. In some embodiments, the cell therapy is enriched in CD4+ T cells. In some embodiments, the cell therapy is enriched in CD8+ T cells. In some embodiments, the T cell therapy is enriched in CD4+ and CD8+ T cells. In some embodiments, the CD4+ and CD8+ T cells of the T cell therapy includes a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells and/or of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells, that is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1. In some embodiments, the CD4+ and CD8+ T cells of the T cell therapy includes a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells. In some embodiments, the ratio is or is approximately 1:1. In some embodiments, the ratio is between approximately 1:3 and approximately 3:1.

[0107] In some embodiments, the T cell therapy is enriched in CD4+ and CD8+ T cells, wherein the administration of the T cell therapy includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition including or enriched in the CD8+ T cells and a second composition including or enriched in the CD4+ T cells.

[0108] In some embodiments, the CD4+ CAR-expressing T cells in the one of the first and second compositions and the CD8+ CAR-expressing T cells in the other of the first and second compositions are present at a defined ratio that is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1; and/or the CD4+ CAR-expressing T cells and the CD8+ CAR-expressing T cells in the first and second compositions are present at a defined ratio, which ratio is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1. In some embodiments, the CD4+ CAR-expressing T cells in the one of the first and second compositions and the CD8+ CAR-expressing T cells in the other of the first and second compositions are present at a defined ratio. In some embodiments, the CD4+ CAR-expressing T cells and the CD8+ CAR-expressing T cells in the first and second compositions are present at a defined ratio. In some embodiments, the ratio is or is approximately 1:1. In some embodiments, the ratio is between approximately 1:3 and approximately 3:1.

[0109] In some embodiments, administration of the T cell therapy includes administration of from or from about 1.times.10.sup.5 to 5.times.10.sup.8 total CAR-expressing T cells, of from or from about 1.times.10.sup.6 to 2.5.times.10.sup.8 total CAR-expressing T cells, of from or from about 5.times.10.sup.6 to 1.times.10.sup.8 total CAR-expressing T cells, of from or from about 1.times.10.sup.7 to 2.5.times.10.sup.8 total CAR-expressing T cells, or of from or from about 5.times.10.sup.7 to 1.times.10.sup.8 total CAR-expressing T cells, each inclusive. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.5 to 5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.6 to 2.5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 5.times.10.sup.6 to 1.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 1.times.10.sup.7 to 2.5.times.10.sup.8 total CAR-expressing T cells. In some embodiments, the cell therapy includes administration of from or from about 5.times.10.sup.7 to 1.times.10.sup.8 total CAR-expressing T cells.

[0110] In some embodiments, administration of the T cell therapy includes administration of at least or at least about 1.times.10.sup.5 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.5 CAR-expressing T cells, at least or at least about 5.times.10.sup.5 CAR-expressing T cells, at least or at least about 1.times.10.sup.6 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.6 CAR-expressing T cells, at least or at least about 5.times.10.sup.6 CAR-expressing T cells, at least or at least about 1.times.10.sup.7 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.7 CAR-expressing T cells, at least or at least about 5.times.10.sup.7 CAR-expressing T cells, at least or at least about 1.times.10.sup.8 CAR-expressing T cells, at least or at least about 2.5.times.10.sup.8 CAR-expressing T cells, or at least or at least about 5.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.5 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.6 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.7 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 1.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 2.5.times.10.sup.8 CAR-expressing T cells. In some embodiments, the cell therapy includes administration of at least or at least about 5.times.10.sup.8 CAR-expressing T cells.

[0111] In some embodiments, administration of the T cell therapy includes administration of at or about 5.times.10.sup.7 total CAR-expressing T cells. In some embodiments, administration of the T cell therapy includes administration of at or about 1.times.10.sup.8 CAR-expressing cells.

[0112] In some embodiments, the CAR includes an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM.

[0113] In some embodiments, the antigen is selected from among .alpha.v.beta.6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer/testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22R.alpha.), IL-13 receptor alpha 2 (IL-13R.alpha.2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1). In some embodiments, the antigen is selected from among CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30. In some embodiments, the antigen is CD19.

[0114] In some embodiments, the intracellular signaling domain includes an intracellular domain of a CD3-zeta (CD3.zeta.) chain. In some embodiments, the intracellular signaling region further includes a costimulatory signaling region. In some embodiments, the costimulatory signaling region includes a signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB. In some embodiments, the costimulatory domain is or includes a signaling domain of CD28. In some embodiments, the costimulatory domain is or includes a signaling domain of 4-1BB. In some embodiments, the costimulatory domain is or includes a signaling domain of human CD28. In some embodiments, the costimulatory domain is or includes a signaling domain of human 4-1BB.

[0115] In some embodiments, for selected subjects and/or subjects identified as having a cancer resistant to treatment with the T cell therapy, the method includes collecting a biological sample from the subject including cells autologous to the subject prior to initiation of administration of the EZH2 inhibitor. In some embodiments, the biological sample from the subject is or includes a whole blood sample, a buffy coat sample, a peripheral blood mononuclear cells (PBMC) sample, an unfractionated T cell sample, a lymphocyte sample, a white blood cell sample, an apheresis product, or a leukapheresis product. In some embodiments, the biological sample from the subject is or includes an apheresis product. In some embodiments, the biological sample from the subject is or includes a leukapheresis product.

[0116] In some embodiments, the method includes, prior to administration of a T cell therapy, administering a lymphodepleting agent or therapy to the subject.

[0117] In some embodiments, if a subject is administered an EZH2 inhibitor, the EZH2 inhibitor is administered to the subject after the lymphodepleting therapy concludes. In some embodiments, the lymphodepleting therapy is completed between 2 and 7 days before the initiation of administration of the T cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy prior to initiation of administration of the cell therapy. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample. In some embodiments, the subject is administered a lymphodepleting therapy after collection of the biological sample and prior to initiation of administration of the cell therapy. In some embodiments, the lymphodepleting therapy concludes between 2 and 7 days before initiation of administration of the cell therapy. In some embodiments, the tumor biopsy sample is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the tumor biopsy sample is obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject. In some embodiments, the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy. In some embodiments, administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

[0118] In some embodiments, the lymphodepleting therapy comprises the administration of fludarabine and/or cyclophosphamide. In some embodiments, the lymphodepleting therapy includes the administration of fludarabine. In some embodiments, the lymphodepleting therapy includes the administration of cyclophosphamide. In some embodiments, the lymphodepleting therapy includes the administration of fludarabine and cyclophosphamide.

[0119] In some embodiments, the lymphodepleting therapy includes administration of cyclophosphamide at about 200-400 mg/m.sup.2, optionally at or about 300 mg/m.sup.2, inclusive, and/or fludarabine at about 20-40 mg/m.sup.2, optionally 30 mg/m.sup.2, daily for 2-4 days, optionally for 3 days, or wherein the lymphodepleting therapy includes administration of cyclophosphamide at about 500 mg/m.sup.2. In some embodiments, the lymphodepleting therapy includes administration of cyclophosphamide at or about 300 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days; and/or the lymphodepleting therapy includes administration of cyclophosphamide at or about 500 mg/m.sup.2 and fludarabine at about 30 mg/m.sup.2 daily for 3 days.

[0120] In some embodiments, the initiation of administration of the inhibitor is within at or about 5 days prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within at or about 1 day prior to initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is concurrent with or on the same day as initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy, optionally wherein the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is no more than 2 days after initiation of administration of the cell therapy. In some embodiments, the initiation of administration of the inhibitor is within 1 day after the initiation of administration of the cell therapy.

[0121] In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen that comprises initiation of administration of the EZH2 inhibitor between about 4 weeks prior to initiation of administration of the cell therapy and about 1 week prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 14 days, at or about 7 days, or at or about 1 day prior to and at or about 14 days, at or about 7 days, or at or about 1 day after initiation of administration of the T cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at a time between at or about 7 days prior to and at or about 2 days prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor at or about 7 days, at or about 5 days, at or about 3 days, at or about 2 days, or at or about 1 day prior to initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises initiation of administration of the inhibitor concurrent with or on the same day as initiation of administration of the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor concurrently with the cell therapy. In some embodiments, the dosing regimen comprises administration of at least one dose of the EZH2 inhibitor on the same day as the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 7 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 5 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 2 days before initiation of administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen, and the dosing regimen comprises ceasing administration of the EZH2 inhibitor at least 1 day before initiation of administration of the cell therapy.

[0122] In some embodiments, the EZH2 inhibitor is administered to the subject before initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject before and until initiation of administration of the lymphodepleting therapy. In some embodiments, the EZH2 inhibitor is administered to the subject after conclusion of administration of the lymphodepleting therapy. In some embodiments, administration of the EZH2 inhibitor resumes after conclusion of the lymphodepleting therapy.

[0123] In some embodiments, a dose of the inhibitor is an amount of the inhibitor between at or about 100 mg and at or about 1600 mg, between at or about 100 mg and at or about 1200 mg, between at or about 100 mg and at or about 800 mg, between at or about 100 mg and at or about 400 mg, between at or about 100 mg and at or about 200 mg, between at or about 200 mg and at or about 1600 mg, between at or about 200 mg and at or about 1200 mg, between at or about 200 mg and at or about 800 mg, between at or about 200 mg and at or about 400 mg, between at or about 400 mg and at or about 1600 mg, between at or about 400 mg and at or about 1200 mg, between at or about 400 mg and at or about 800 mg, between at or about 800 mg and at or about 1600 mg, between at or about 800 mg and at or about 1200 mg, between at or about 1200 mg and at or about 1600 mg, each inclusive. In some embodiments, a dose is about 200 mg. In some embodiments, a dose is about 400 mg. In some embodiments, a dose is about 800 mg.

[0124] In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 800 mg of the inhibitor per day. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 1600 mg of the inhibitor per day. In some embodiments, the EZH2 inhibitor is administered in a dosing regimen including administering about 2400 mg of the inhibitor per day.

[0125] In some embodiments, the inhibitor is administered in a dosing regimen that comprises two doses each day (twice daily dosing). In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 100 mg and at or about 1600 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 200 mg and at or about 1200 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is between at or about 400 mg and at or about 800 mg, inclusive. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 200 mg. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 400 mg. In some embodiments, each dose of the twice daily dosing of the inhibitor is at or about 800 mg.

[0126] In some embodiments, the inhibitor is administered in a dosing regimen that includes three doses each day (thrice daily dosing). In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 100 mg and at or about 1600 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 200 mg and at or about 1200 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is between at or about 400 mg and at or about 800 mg, inclusive. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 200 mg. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 400 mg. In some embodiments, each dose of the thrice daily dosing of the inhibitor is at or about 800 mg.

[0127] In some embodiments, the EZH2 inhibitor is administered for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to five months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to four months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered for up to one month after the initiation of the administration of the cell therapy. In some embodiments, the EZH2 inhibitor is administered until the subject exhibits a complete response. In some embodiments, the EZH2 inhibitor is administered until the subject exhibits disease progression. In some embodiments, administration of the EZH2 inhibitor is discontinued if the subject exhibits clinical remission.

[0128] In some embodiments, the inhibitor inhibits wild type EZH2 and/or mutant EZH2. In some embodiments, the inhibitor inhibits wild type EZH2. In some embodiments, the inhibitor inhibits mutant EZH2, optionally wherein the mutation is a gain-of-function mutation. In some embodiments, EZH2 includes one or more mutations selected from among Y641C, Y641F, Y641H, Y641N, Y641S, Y646C, Y646F, Y646H, Y646N, Y646S, A677G, A682G, A687V, A692V, K634E, V637A, and V679M. In some embodiments, the mutation increases trimethylation of histone 3 at lysine 27.

[0129] In some embodiments, the inhibitor inhibits EZH2 with a half-maximal inhibitory concentration (IC.sub.50) for wild type and/or mutant EZH2 that is less than or less than about 1000 nM, 900 nM, 800 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 10 nM, or less than or less than about 5 nM. In some embodiments, the half-maximal inhibitory concentration (IC.sub.50) of the inhibitor for EZH2 is lower than the half-maximal inhibitory concentration (IC.sub.50) of the inhibitor for EZH1, optionally at least 2 times lower, at least 5 times lower, 10 times lower, at least 100 times lower, at least 1,000 times lower, at least 5,000 times lower, at least 10,000 times lower, or at least 20,000 times lower.

[0130] In some embodiments, the inhibitor is selected from among the group consisting of tazemetostat (EPZ-6438), CPI-1205, GSK343, GSK126, and valemetostat (DS-3201b). In some embodiments, the inhibitor is tazemetostat (EPZ-6438). In some embodiments, the inhibitor is CPI-1205.

[0131] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a bladder cancer, a breast cancer, a melanoma, or a prostate cancer. In some embodiments, the solid tumor is a prostate cancer. In some embodiments, the prostate cancer is a castration-resistant prostate cancer (CRPC).

[0132] In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a myeloma, leukemia or lymphoma. In some embodiments, the cancer is an acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), a small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), a large B cell lymphoma. In some embodiments, the cancer is a non-Hodgkin lymphoma (NHL). In some embodiments, the NHL is a follicular lymphoma (FL). In some embodiments, the NHL is a diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the DLBCL is not an activated B-cell (ABC) subtype of DLBC.

[0133] In some embodiments, a subject is selected for treatment with the EZH2 inhibitor as a subject that has a DLBCL. In some embodiments, the subject is selected for treatment with the EZH2 inhibitor as a subject that has a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the subject is selected from treatment with the EZH2 inhibitor as a subject having a pre-treatment tumor biopsy with a DLBCL-like gene expression signature. In some embodiments, the subject is selected from treatment as a subject having a pre-treatment tumor biopsy gene expression signature associated with a progressive disease (PD) response 3 months post-treatment with cell therapy.

[0134] In some embodiments, the method comprises selecting the subject for treatment with the EZH2 inhibitor as a subject that has a DLBCL. In some embodiments, the method comprises selecting the subject for treatment with the EZH2 inhibition as a subject that has a germinal center B-cell (GCB) subtype of DLBCL. In some embodiments, the method comprises selecting a subject having a pre-treatment tumor biopsy with a DLBCL-like gene expression signature. In some embodiments, the method comprises selecting a subject having a pre-treatment tumor biopsy gene expression signature associated with a progressive disease (PD) response 3 months post-treatment with cell therapy.

[0135] In some embodiments, the subject has relapsed following remission after treatment with, or become refractory to, failed and/or was intolerant to treatment with a prior therapy for treating the cancer. In some embodiments, the cancer is resistant to treatment with the cell therapy alone.

[0136] In some embodiments, the cancer exhibits overexpression of EZH2 and/or expression of EZH2 comprising one or more mutations selected from among Y641C, Y641F, Y641H, Y641N, Y641S, Y646C, Y646F, Y646H, Y646N, Y646S, A677G, A682G, A687V, A692V, K634E, V637A, and V679M, optionally wherein the mutation is a gain-of-function mutation. In some embodiments, the cancer exhibits overexpression of EZH2. In some embodiments, the cancer exhibits one or more mutations in the gene encoding EZH2. In some embodiments, the one or more mutations is a gain-of-function mutation.

[0137] In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice or thrice daily daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to six months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice or thrice daily daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to three months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor for up to two months after the initiation of the administration of the cell therapy. In some embodiments, if the subject is administered an EZH2 inhibitor, the dosing regimen of the inhibitor includes administration of the inhibitor, optionally twice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor, optionally twice daily or thrice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor twice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of the inhibitor comprises administration of the inhibitor thrice daily, for up to two months after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, if the subject is administered an EZH2 inhibitor, the dosing regimen of inhibitor includes administration of the inhibitor, optionally twice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor twice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor thrice daily, for up to 1 month after the initiation of the administration of the cell therapy. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor until the subject exhibits clinical remission. In some embodiments, if the subject is administered an EZH2 inhibitor, administration of the inhibitor in the dosing regimen is discontinued if the subject exhibits clinical remission. In some embodiments, the dosing regimen of inhibitor includes administration of the inhibitor until the subject exhibits disease progression In some embodiments, administration of the inhibitor in the dosing regimen is discontinued if the subject exhibits disease progression.

[0138] In some embodiments, in a plurality of subjects treated, infiltration of the CAR-expressing T cells of the cell therapy into a tumor microenvironment (TME) is increased, compared to a method that does not involve the administration of the inhibitor. In some embodiments, the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject.

[0139] In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E4 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E5 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is increased for a gene given in Table E2B in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E2 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E3 in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, gene transcription and/or protein expression is decreased for a gene given in Table E2A in the subject, compared to gene transcription and/or protein expression of the gene in the subject prior to administration of the inhibitor.

[0140] In some of any of the provided embodiments, the one or more first genes is selected from a gene set forth in Table E2. In some embodiments, the one or more first genes is selected from a gene set forth in Table E2A. In some embodiments, the one or more second genes is a T cell marker, optionally CD3.epsilon.. In some of any of the provided embodiments, the one or more second genes is selected from a gene set forth in Table E4. In some embodiments, the one or more second genes is selected from a gene set forth in Table E2B.

[0141] In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E4 is more upregulated or less downregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E5 is more upregulated or less downregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2B is more upregulated or less downregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2 is more downregulated or less upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E3 is more downregulated or less upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor. In some embodiments, in a plurality of subjects treated, expression of the gene set given by Table E2A is more downregulated or less upregulated in the subject, compared to expression of the gene set in the subject prior to administration of the inhibitor.

[0142] In some embodiments, the one or more first gene set is given by Table E2. In some embodiments, the one or more first gene set is given by Table E2A. In some embodiments, the one or more second gene set is given by Table E4. In some embodiments, the one or more second gene set is given by Table E2B.

[0143] In some embodiments, a plurality of genes selected from genes included in one or more of the HALLMARK_E2F_TARGETS, HALLMARK_G2M_CHECKPOINT, HALLMARK_MTORC1_SIGNALING, and HALLMARK_MYC_TARGETS_V2 gene sets are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) predicted to exhibit PD in response to a T cell therapy (e.g. a CAR T cell therapy). In some embodiments, a plurality of genes selected from genes included in one or more of the HALLMARK_E2F_TARGETS, HALLMARK_G2M_CHECKPOINT, HALLMARK_MTORC1_SIGNALING, and HALLMARK_MYC_TARGETS_V2 gene sets are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) selected for treatment with a combination of an EZH2 inhibitor and a T cell therapy (e.g. a CAR T cell therapy).

[0144] In some embodiments, a plurality of genes selected from genes included in each of the HALLMARK_E2F_TARGETS, HALLMARK_G2M_CHECKPOINT, HALLMARK_MTORC1_SIGNALING, HALLMARK_MYC_TARGETS_V2 gene sets are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) predicted to exhibit PD in response to a T cell therapy (e.g. a CAR T cell therapy). In some embodiments, a plurality of genes selected from genes included in each of the HALLMARK_E2F_TARGETS, HALLMARK_G2M_CHECKPOINT, HALLMARK_MTORC1_SIGNALING, HALLMARK_MYC_TARGETS_V2 gene sets are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) selected for treatment with a combination of an EZH2 inhibitor and a T cell therapy (e.g. a CAR T cell therapy).

[0145] In some embodiments, a plurality of genes selected from genes included in the HALLMARK_INTERFERON_ALPHA_RESPONSE gene set are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) predicted to exhibit CR in response to a T cell therapy (e.g. a CAR T cell therapy). In some embodiments, a plurality of genes selected from genes included in the HALLMARK_INTERFERON_ALPHA_RESPONSE gene set are upregulated in a subject (e.g. in a pre-treatment tumor biopsy) selected for treatment with a combination of an EZH2 inhibitor a T cell therapy (e.g. a CAR T cell therapy).

[0146] In any of the provided embodiments, gene set expression is determined by a method comprising gene set enrichment analysis (GSEA).

[0147] In some embodiments, at least 35%, at least 40% or at least 50% of subjects treated according to the method achieve a complete response (CR) that is durable, or is durable in at least 60, 70, 80, 90, or 95% of subjects achieving the CR, for at or greater than 6 months or at or greater than 9 months; and/or wherein at least 60, 70, 80, 90, or 95% of subjects achieving a CR by six months remain in response, remain in CR, and/or survive or survive without progression, for greater at or greater than 3 months and/or at or greater than 6 months and/or at greater than nine months; and/or at least 50%, at least 60% or at least 70% of the subjects treated according to the method achieve objective response (OR) optionally wherein the OR is durable, or is durable in at least 60, 70, 80, 90, or 95% of subjects achieving the OR, for at or greater than 6 months or at or greater than 9 months; and/or wherein at least 60, 70, 80, 90, or 95% of subjects achieving an OR by six months remain in response or surviving for greater at or greater than 3 months and/or at or greater than 6 months.

[0148] In some embodiments, the biological sample is a tumor biopsy, optionally a lymph node biopsy. In some embodiments, the tumor biopsy sample is obtained before a lymphodepleting therapy is administered to the subject. In some embodiments, the tumor biopsy sample is obtained within 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 16 hours before, 12 hours before, 6 hours before, 2 hours before, or 1 hour before the lymphodepleting therapy is administered to the subject.

[0149] In some embodiments, the subject is a human.


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