Building IP: JUNO Patent Appl "BCMA-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL ... | BMY Message Board Posts


Bristol-Myers Squibb Co.

  BMY website

BMY   /  Message Board  /  Read Message

 

 






Keyword
Subject
Between
and
Rec'd By
Authored By
Minimum Recs
  
Previous Message  Next Message    Post Message    Post a Reply return to message boardtop of board
Msg  10965 of 11279  at  3/23/2023 9:07:18 AM  by

JBWIN


Building IP: JUNO Patent Appl "BCMA-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL ...

 

BCMA-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL COMPOSITIONS AND METHODS AND USES THEREOF

DOCUMENT ID

US 20230087953 A1

DATE PUBLISHED

2023-03-23

INVENTOR INFORMATION

NAME

CITY

STATE

ZIP CODE

COUNTRY

WESTOBY; Matthew
Seattle
WA
N/A
US
BRIGGS; Adrian Wrangham
Seattle
WA
N/A
US
KUGLER; David G.
Seattle
WA
N/A
US
CASPARY; Robert Guy
Seattle
WA
N/A
US
CHAN; Calvin
Seattle
WA
N/A
US
VARUN; Divya
Seattle
WA
N/A
US
GERMEROTH; Lothar
Munich
N/A
N/A
DE
STEMBERGER; Christian
Munich
N/A
N/A
DE
POLTORAK; Mateusz Pawel
Munich
N/A
N/A
DE
BASHOUR; Keenan
Seattle
WA
N/A
US
BATUREVYCH; Oleksandr
Seattle
WA
N/A
US
KILAVUZ; Nurgul
Summit
NJ
N/A
US
HEGE; Kristen
Summit
NJ
N/A
US
BURGESS; Michael
Summit
NJ
N/A
US
WU; Kaida
Summit
NJ
N/A
US
SALMON; Ruth Amanda
Seattle
WA
N/A
US
KOEGEL; Ashley
Summit
NJ
N/A
US

APPLICANT INFORMATION

NAME
Juno Therapeutics, Inc.
CITY
Seattle
STATE
WA
ZIP CODE
N/A
COUNTRY
US
AUTHORITY
N/A
TYPE
assignee

ASSIGNEE INFORMATION

NAME
Juno Therapeutics, Inc.
CITY
Seattle
STATE
WA
ZIP CODE
N/A
COUNTRY
US
TYPE CODE
02

APPLICATION NO

17/799239

DATE FILED

2021-02-11

DOMESTIC PRIORITY (CONTINUITY DATA)

us-provisional-application US 62975731 20200212

US CLASS CURRENT:

1/1

CPC CURRENT

TYPE

CPC

DATE

CPCI
2018-01-01
CPCI
2013-01-01
CPCI
2013-01-01

Abstract

Provided in some aspects are compositions of cells for treating subjects with disease and conditions such as multiple myeloma (MM), and related methods, compositions, uses and articles of manufacture. In some embodiments, the disease or condition is a relapsed or refractory multiple myeloma (r/r MM). The cells generally express recombinant receptors such as chimeric antigen receptors (CARs) for targeting an antigen, such as BCMA, on cells of the myeloma.

Background/Summary

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisional application No. 62/975,731 filed Feb. 12, 2020, entitled “BCMA-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL COMPOSITIONS AND METHODS AND USES THEREOF,” the contents of which are incorporated by reference in their entirety.

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 735042023540SEQLIST.txt, created Feb. 10, 2021, which is 184 kilobytes 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 adoptive cell therapy involving the administration of compositions of cells for treating subjects with disease and conditions such as multiple myeloma (MM), and related methods, compositions, uses and articles of manufacture.

BACKGROUND

[0004] Various immunotherapy and/or cell therapy methods are available for treating diseases and conditions. 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) can be beneficial in the treatment of cancer or other diseases or disorders. Improved approaches are needed. Provided are methods, uses and articles of manufacture that meet such needs.

SUMMARY

[0005] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; and at least or at least about 80% of the cells in the composition are CD3.sup.+ cells.

[0006] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; and at least or at least about 90% of the cells in the composition are CD3.sup.+ cells.

[0007] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and at least or at least about 80% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype.

[0008] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+ and/or at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+.

[0009] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is less than or less than about 0.9.

[0010] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method comprising administering to a subject having or suspected of having a MM a composition comprising engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein: the composition comprises CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.

[0011] In some of any embodiments, the composition comprises between at or about 50×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition comprises between at or about 70×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition comprises between at or about 80×10.sup.6 CAR-expressing T cells and at or about 200×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition comprises between at or about 80×10.sup.6 CAR-expressing T cells and at or about 160×10.sup.6 CAR-expressing T cells, inclusive.

[0012] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 40×10.sup.6 CAR-expressing T cells, inclusive; and at least or at least about 80% of the cells in the composition are CD3.sup.+ cells.

[0013] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 80×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 90% of the cells in the composition are CD3.sup.+ cells.

[0014] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 10×10.sup.6 CAR-expressing T cells, inclusive; and at least or at least about 80% of the cells in the composition are CD3.sup.+ cells.

[0015] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 80×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and at least or at least about 80% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype.

[0016] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 100×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+ and/or at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+.

[0017] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 20×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and at least or at least about 80% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype.

[0018] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 80×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is less than or less than about 0.9.

[0019] In one aspect, provided herein is a method of treating a multiple myeloma (MM), the method including administering to a subject having or suspected of having a MM a composition including engineered T cells expressing a chimeric antigen receptor (CAR) that targets B cell maturation antigen (BCMA), wherein the composition includes CD8.sup.+ T cells expressing the CAR and CD4.sup.+ T cells expressing the CAR; the composition includes between at or about 5×10.sup.6 CAR-expressing T cells and at or about 80×10.sup.6 CAR-expressing T cells, inclusive; at least or at least about 80% of the cells in the composition are CD3.sup.+ cells; and the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.

[0020] In some of any embodiments, the composition comprises CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR at a ratio between about 1:2.5 and about 5:1. In some of any embodiments, the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 80×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 40×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition comprises between at or about 5×10.sup.6 CAR-expressing T cells and at or about 20×10.sup.6 CAR-expressing T cells, inclusive.

[0021] In some of any embodiments, the composition may include CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR at a ratio between about 1:2 and about 4:1, between about 1:1.5 and about 2:1, or at or at about 1:1. In some of any embodiments, the composition may include CD4.sup.+ T cells expressing the CAR and CD8.sup.+ T cells expressing the CAR at a ratio between about 5:1 and about 2:1, between about 4:1 and about 2:1, between about 3:1 and about 2:1, at or at about 5:1, at or at about 4:1, at or at about 3:1, or at or at about 2:1. In some of any embodiments, the composition may include between at or about 5×10.sup.6 CAR-expressing T cells and at or about 10×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition may include between at or about 10×10.sup.6 CAR-expressing T cells and at or about 20×10.sup.6 CAR-expressing T cells, inclusive. In some of any embodiments, the composition may include at or about 20×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include or about 30×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include at or about 40×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include at or about 10×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include at or about 60×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include at or about 80×10.sup.6 CAR-expressing T cells. In some of any embodiments, the composition may include at or about 160×10.sup.6 CAR-expressing T cells.

[0022] In some of any embodiments, at least or at least about 90% of the cells in the composition are CD3.sup.+ cells.

[0023] In some of any embodiments, at least or at least about 91%, at least or at least about 92%, at least or at least about 93%, at least or at least about 94%, at least or at least about 95%, or at least or at least about 96% of the cells in the composition are CD3.sup.+ cells. In some of any embodiments, between at or about 2% and at or about 30% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some of any embodiments, between at or about 5% and at or about 10% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some of any embodiments, between at or about 10% and at or about 15% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some of any embodiments, between at or about 15% and at or about 20% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some of any embodiments, between at or about 20% and at or about 30% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some of any embodiments, at or about 5%, at or about 10%, at or about 15%, at or about 20%, at or about 25%, or at or about 30% of the CAR.sup.+ T cells in the composition express a marker of apoptosis, optionally Annexin V or active Caspase 3. In some embodiments, the marker of apoptosis is Annexin V. In some embodiments, the marker of apoptosis is active Caspase 3.

[0024] In some of any embodiments, at least or at least about 80% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype.

[0025] In some of any embodiments, between at or about 80% and at or about 85% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype. In some of any embodiments, between at or about 85% and at or about 90% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype. In some of any embodiments, between at or about 90% and at or about 95% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype. In some of any embodiments, between at or about 95% and at or about 99% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype. In some of any embodiments, at or about 85%, at or about 90%, at or about 95%, or at or about 99% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype.

[0026] In some of any embodiments, the at least or at least about 80% of the CAR.sup.+ T cells in the composition that are of a naïve-like or central memory phenotype are surface positive for a marker expressed on naïve-like or central memory T cells. In some of any embodiments, the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7.

[0027] In some of any embodiments, the at least or at least about 80% of the CAR.sup.+ T cells in the composition that are of a naïve-like or central memory phenotype have a phenotype selected from CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, or CD62L.sup.−CCR7.sup.+. In some of any embodiments, between at or about 80% and at or about 85%, between at or about 85% and at or about 90%, between at or about 90% and at or about 95%, between at or about 95% and at or about 99% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype selected from CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, or CD62L.sup.− CCR7.sup.+. In some of any embodiments, at or about 80%, at or about 85%, at or about 90%, at or about 95%, or at or about 99% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype selected from CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, or CD62L.sup.−CCR7.sup.+. In some of any embodiments, at or about 80%, at or about 85%, at or about 90%, at or about 95%, or at or about 99% of the CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+.

[0028] In some of any embodiments, at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 60% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 70% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 80% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 85% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−.

[0029] In some of any embodiments, at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 60% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 70% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 80% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 85% of the CD4.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+.

[0030] In some of any embodiments, at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 60% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 70% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 80% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 85% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−.

[0031] In some of any embodiments, at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 60% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 70% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 80% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 85% of the CD8.sup.+CAR.sup.+ T cells in the composition are of a naïve-like or central memory phenotype that is CD27.sup.+CCR7.sup.+.

[0032] In some of any embodiments, at least or at least about 80% of the CAR.sup.+ T cells in the composition are surface positive for a marker expressed on naïve-like or central memory T cells. In some of any embodiments, the marker expressed on naïve-like or central memory T cell is selected from the group consisting of CD45RA, CD27, CD28, and CCR7. In some of any embodiments, at least or at least about 80% of the CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, and/or CD62L.sup.− CCR7.sup.+. In some of any embodiments, between at or about 80% and at or about 85%, between at or about 85% and at or about 90%, between at or about 90% and at or about 95%, between at or about 95% and at or about 99% of the CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, and/or CD62L.sup.−CCR7.sup.+. In some of any embodiments, at or about 80%, at or about 85%, at or about 90%, at or about 95%, or at or about 99% of the CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+, CD27.sup.+CCR7.sup.+, and/or CD62L.sup.−CCR7.sup.+. In some of any embodiments, at or about 80%, at or about 85%, at or about 90%, at or about 95%, or at or about 99% of the CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 60% of the CD4.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−.

[0033] In some of any embodiments, at least or at least about 70% of the CD4.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 80% of the CD4.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 85% of the CD4.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 50% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 60% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 70% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 80% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 85% of the CD4.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 60% of the CD8.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 70% of the CD8.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 80% of the CD8.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 85% of the CD8.sup.+CAR.sup.+ T cells in the composition are CCR7.sup.+CD45RA.sup.+ or CCR7.sup.+CD45RA.sup.−. In some of any embodiments, at least or at least about 50% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 60% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 70% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 80% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+. In some of any embodiments, at least or at least about 85% of the CD8.sup.+CAR.sup.+ T cells in the composition are CD27.sup.+CCR7.sup.+.

[0034] In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is less than or less than about 0.9.

[0035] In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is between at or about 0.9 and at or about 0.8. In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is less than or less than about 0.8. In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is between at or about 0.8 and at or about 0.7. In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is between at or about 0.7 and at or about 0.6. In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is between at or about 0.6 and at or about 0.5. In some of any embodiments, the fraction of integrated vector copy number (iVCN) to total VCN in the CAR.sup.+ T cells in the composition, on average, is between at or about 0.5 and at or about 0.4.

[0036] In some of any embodiments, the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 0.4 copies per diploid genome and 2.0 copies per diploid genome, inclusive.

[0037] In some of any embodiments, the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 0.8 copies per diploid genome and 2.0 copies per diploid genome, inclusive. In some of any embodiments, the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 0.8 copies per diploid genome and 1.0 copies per diploid genome, inclusive. In some of any embodiments, the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 1.0 copies per diploid genome and 1.5 copies per diploid genome, inclusive. In some of any embodiments, the integrated vector copy number (iVCN) of the CAR.sup.+ T cells in the composition, on average, is between or between about 1.5 copies per diploid genome and 2.0 copies per diploid genome, inclusive.

[0038] In some of any embodiments, at or prior to the administration of the composition of engineered T cells, the subject has received at least 3 prior antimyeloma treatment regimens. In some of any embodiments, at or prior to the administration of the composition of engineered T cells, the subject has received three or more therapies, optionally four or more prior therapies, selected from among an autologous stem cell transplant (ASCT); an immunomodulatory agent; a proteasome inhibitor; and an anti-CD38 agent, unless the subject was not a candidate for or was contraindicated for one or more of the therapies. In some of any embodiments, at or prior to the administration of the composition of engineered T cells, the subject has received three or more therapies, optionally four or more prior therapies, optionally selected from among an autologous stem cell transplant (ASCT); an immunomodulatory agent and a proteasome inhibitor, either alone or in combination; and an anti-CD38 agent. In some of any embodiments, at or prior to the administration of the composition of engineered T cells, the subject has received all three of the following therapies including autologous stem cell transplant (ASCT); a regimen including an immunomodulatory agent and a proteasome inhibitor; and an anti-CD38 agent.

[0039] In some of any embodiments, at or prior to the administration of the composition comprising engineered T cells, the subject has received all three of the following antimyeloma treatment regimens: autologous stem cell transplant (ASCT); an immunomodulatory agent and/or a proteasome inhibitor, either alone or in combination; and an anti-CD38 agent. In some of any embodiments, induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen for purpose of determining the number of prior antimyeloma treatment regimens.

[0040] In some of any embodiments, at or prior to the administration of the composition comprising engineered T cells, the subject is refractory to the last antimyeloma treatment regimen. In some of any embodiments, refractory myeloma is defined as documented progressive disease during or within 12 months, measured from the last dose, of completing treatment with the last anti-myeloma treatment regimen. In some of any embodiments, refractory myeloma is defined as documented progressive disease during or within 60 days, measured from the last dose, of completing treatment with the last anti-myeloma treatment regimen.

[0041] In some of any embodiments, the immunomodulatory agent is selected from among thalidomide, lenalidomide, and pomalidomide, either alone or in combination. In some of any embodiments, the proteasome inhibitor is selected from among bortezomib, carfilzomib, and ixazomib, either alone or in combination.

[0042] In some of any embodiments, the subject has undergone at least one complete cycle of treatment with the antimyeloma treatment regimen comprising the immunomodulatory agent and/or the proteasome inhibitor unless progressive disease was the best response to the antimyeloma treatment regimen. In some of any embodiments, the subject has undergone at least two consecutive cycles of treatment with the antimyeloma treatment regimen comprising the immunomodulatory agent and/or the proteasome inhibitor unless progressive disease was the best response to the antimyeloma treatment regimen.

[0043] In some of any embodiments, the anti-CD38 agent is an anti-CD38 antibody. In some of any embodiments, the anti-CD38 agent is or comprises daratumumab. In some of any embodiments, the anti-CD38 agent is used as part of a combination regimen or as a monotherapy.

[0044] In some of any embodiments, at the time of the administration of the composition comprising engineered T cells, the subject has not had an active or a history of plasma cell leukemia (PCL). In some of any embodiments, at the time of the administration, the subject has relapsed or has been refractory following at least 3 or at least 4 prior antimyeloma treatment regimen. In some of any embodiments, at the time of the administration, the subject has a time from diagnosis of multiple myeloma of approximately 4 years or between 2 and 15 years or between 2 and 12 years. In some of any embodiments, at the time of the administration, the subject has received about 10 or between 3 and 15 or between 4 and 15 prior antimyeloma treatment regimen. In some of any embodiments, at the time of the administration, the subject has been refractory to or not responded to bortezomib, carfilzomib, lenalidomide, pomalidomide, and/or an anti-CD38 monoclonal antibody. In some of any embodiments, at the time of the administration, the subject has had a prior autologous stem cell transplant. In some of any embodiments, at the time of the administration, the subject has not had a prior autologous stem cell transplant (ASCT) due to ineligibility for ASCT, optionally ineligibility due to age or other documented reasons. In some of any embodiments, at the time of the administration, the subject has IMWG high risk cytogenetics. In some of any embodiments, the subject does not have a central nervous system involvement of MM, plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, and/or clinically significant amyloidosis. In some of any embodiments, the subject has not received a prior CAR T cell or genetically-modified T cell therapy. In some of any embodiments, the subject has not received a prior BCMA-targeted therapy such as an anti-BCMA monoclonal antibody or bispecific antibody.

[0045] In some of any embodiments, the method further comprises obtaining a leukapheresis sample from the subject for manufacturing the composition comprising engineered T cells.

[0046] In some of any embodiments, the subject has not received a therapeutic dose of a corticosteroid, optionally within at or about 14 days prior to the time of leukapheresis. In some of any embodiments, the subject has not received an immunosuppressive therapy within 4 weeks of leukapheresis, optionally wherein the immunosuppressive therapy comprises a calcineurin inhibitor, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R. In some of any embodiments, the subject has not received a autologous stem-cell transplant within at or about 6 months prior to the time of leukapheresis.

[0047] In some of any embodiments, the subject has not achieved complete remission (CR) in response to a prior therapy. In some of any embodiments, the subject has not achieved an objective response (partial response (PR) or better) in response to a prior therapy. In some of any embodiments, the subject is or has been identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

[0048] In some of any embodiments, the CAR may include an extracellular antigen-binding domain, including a variable heavy chain (V.sub.H) including a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within the sequence set forth in SEQ ID NO: 116 and a variable light chain (V.sub.L) including a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within the sequence set forth in SEQ ID NO: 119; a V.sub.H including a CDR-H1, a CDR-H2 and a CDR-H3 sequences set forth in SEQ ID NOS:97, 101 and 103, respectively, and a V.sub.L including a CDR-L1, a CDR-L2 and a CDR-L3 sequences set forth in SEQ ID NOS:105, 107 and 108, respectively; a V.sub.H including a CDR-H1, a CDR-H2 and a CDR-H3 sequences set forth in SEQ ID NOS:96, 100 and 103, respectively, and a V.sub.L including a CDR-L1, a CDR-L2 and a CDR-L3 sequences set forth in SEQ ID NOS:105, 107 and 108, respectively; a V.sub.H including a CDR-H1, a CDR-H2 and a CDR-H3 sequences set forth in SEQ ID NOS:95, 99 and 103, respectively, and a V.sub.L including a CDR-L1, a CDR-L2 and a CDR-L3 sequences set forth in SEQ ID NOS: 105, 107 and 108, respectively; a V.sub.H including a CDR-H1, a CDR-H2 and a CDR-H3 sequences set forth in SEQ ID NOS:94, 98 and 102, respectively, and a V.sub.L including a CDR-L1, a CDR-L2 and a CDR-L3 sequences set forth in SEQ ID NOS: 104, 106 and 108, respectively; or a V.sub.H including the amino acid sequence of SEQ ID NO: 116 and a V.sub.L including the amino acid sequence of SEQ ID NO: 119; and a spacer including an IgG4/2 chimeric hinge or a modified IgG4 hinge; an IgG2/4 chimeric C.sub.H2 region; and an IgG4 C.sub.H3 region, which optionally is about 228 amino acids in length; optionally wherein the spacer is set forth in SEQ ID NO: 174; and a transmembrane domain, optionally a transmembrane domain from a human CD28; and an intracellular signaling region including a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and a costimulatory signaling region including an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the spacer is the spacer set forth in SEQ ID NO:174.

[0049] In some of any embodiments, the V.sub.H is or may include the amino acid sequence of SEQ ID NO: 116; and the V.sub.L is or includes the amino acid sequence of SEQ ID NO: 119. In some of any embodiments, the extracellular antigen-binding domain may include an scFv. In some of any embodiments, the V.sub.H and the V.sub.L are joined by a flexible linker. In some of any embodiments, the scFv may include a linker including the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:1). In some of any embodiments, the V.sub.H is carboxy-terminal to the V.sub.L. In some of any embodiments, the scFv comprises a linker comprising the amino acid sequence SRGGGGSGGGGSGGGGSLEMA (SEQ ID NO:255)

[0050] In some of any embodiments, the extracellular antigen-binding domain may include the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 114. In some of any embodiments, the extracellular antigen-binding domain may include the amino acid sequence of SEQ ID NO: 114.

[0051] In some of any embodiments, a nucleic acid encoding the extracellular antigen-binding domain may include the sequence of nucleotides of SEQ ID NO:113; a sequence of nucleotides that has at least 90% sequence identity thereto; or a degenerate sequence of either of the preceding sequences. In some of any embodiments, the nucleic acid encoding the extracellular antigen-binding domain may include the sequence of nucleotides of SEQ ID NO:115. In some of any embodiments, the V.sub.H is amino-terminal to the V.sub.L.

[0052] In some of any embodiments, the cytoplasmic signaling domain is or may include the sequence set forth in SEQ ID NO:143 or a sequence of amino acids that has at least 90% sequence identity to SEQ ID NO:143. In some of any embodiments, the costimulatory signaling region may include an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. In some of any embodiments, the costimulatory signaling region may include an intracellular signaling domain of 4-1BB, optionally human 4-1BB. In some of any embodiments, the costimulatory signaling region is or may include the sequence set forth in SEQ ID NO:4 or a sequence of amino acids that has at least 90% sequence identity to the sequence set forth in SEQ ID NO: 4. In some of any embodiments, the costimulatory signaling region is between the transmembrane domain and the cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain.

[0053] In some of any embodiments, the transmembrane domain is or may include a transmembrane domain from human CD28. In some of any embodiments, the transmembrane domain is or may include the sequence set forth in SEQ ID NO:138 or a sequence of amino acids that has at least 90% sequence identity to SEQ ID NO:138.

[0054] In some of any embodiments, the CAR may include from its N to C terminus in order: the extracellular antigen-binding domain, the spacer, the transmembrane domain and the intracellular signaling region. In some of any embodiments, the CAR may include an extracellular antigen-binding domain, including a variable heavy chain (V.sub.H) including a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained within the sequence set forth in SEQ ID NO: 116 and a variable light chain (V.sub.L) including a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within the sequence set forth in SEQ ID NO: 119; a spacer including a modified IgG4 hinge; an IgG2/4 chimeric C.sub.H2 region; and an IgG4 C.sub.H3 region, that is about 228 amino acids in length; a transmembrane domain from a human CD28; and an intracellular signaling region including a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and a costimulatory signaling region including an intracellular signaling domain of a 4-1BB.

[0055] In some of any embodiments, the CAR may include an extracellular antigen-binding domain, including the sequence set forth in SEQ ID NO: 114 or a sequence of amino acids having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 114; a spacer including the sequence set forth in SEQ ID NO: 174 or a sequence of amino acids that has at least 90% sequence identity to SEQ ID NO:174; a transmembrane domain including the sequence set forth in SEQ ID NO:138 or a sequence of amino acids that has at least 90% sequence identity to SEQ ID NO:138; and an intracellular signaling region including a cytoplasmic signaling including the sequence set forth in SEQ ID NO:143 or a sequence of amino acids that has at least 90% sequence identity to SEQ ID NO:143 and a costimulatory signaling region including the sequence set forth in SEQ ID NO:4 or a sequence of amino acids that has at least 90% sequence identity to the sequence set forth in SEQ ID NO: 4.

[0056] In some of any embodiments, the CAR may include an extracellular antigen-binding domain, including the sequence set forth in SEQ ID NO: 114; a spacer including the sequence set forth in SEQ ID NO: 174; a transmembrane domain including the sequence set forth in SEQ ID NO:138; and an intracellular signaling region including a cytoplasmic signaling including the sequence set forth in SEQ ID NO:143 and a costimulatory signaling region including the sequence set forth in SEQ ID NO:4. In some of any embodiments, the CAR may include an extracellular antigen-binding domain set forth in SEQ ID NO: 114; a spacer set forth in SEQ ID NO: 174; a transmembrane domain set forth in SEQ ID NO:138; and an intracellular signaling region including a cytoplasmic signaling set forth in SEQ ID NO:143 and a costimulatory signaling region set forth in SEQ ID NO:4. In some of any embodiments, CAR may include the sequence set forth in SEQ ID NO:19. In some of any embodiments, the sequence of the CAR is set forth in SEQ ID NO:19.

[0057] In some of any embodiments, following expression of a polynucleotide encoding the CAR in a human cell, optionally a human T cell, the transcribed RNA, optionally messenger RNA (mRNA), from the polynucleotide, exhibits at least 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some of any embodiments, the CAR is encoded by a polynucleotide sequence comprising the sequence set forth in SEQ ID NO: 13 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In some of any embodiments, the CAR is encoded by a polynucleotide sequence comprising the sequence set forth in SEQ ID NO: 13.

[0058] In some of any embodiments, the binding of the extracellular antigen-binding domain and/or the CAR, or a measure indicative of function or activity of the CAR following exposure to cells expressing surface BCMA, is not reduced or blocked or is not substantially reduced or blocked in the presence of a soluble or shed form of BCMA. In some of any embodiments, the concentration or amount of the soluble or shed form of the BCMA corresponds to a concentration or amount present in serum or blood or plasma of the subject or of a multiple myeloma patient, or on average in a multiple myeloma patient population, or at a concentration or amount of the soluble or shed BCMA at which the binding or measure is reduced or blocked, or is substantially reduced or blocked, for cells expressing a reference anti-BCMA recombinant receptor, optionally a reference anti-BCMA CAR, in the same assay.

[0059] In some of any embodiments, prior to the administration, the subject has received a lymphodepleting therapy comprising the administration of fludarabine at or about 20-40 mg/m.sup.2 body surface area of the subject, optionally at or about 30 mg/m.sup.2, daily, for 2-4 days, and/or cyclophosphamide at or about 200-400 mg/m.sup.2 body surface area of the subject, optionally at or about 300 mg/m.sup.2, daily, for 2-4 days. In some of any embodiments, prior to the administration, the subject has received a lymphodepleting therapy comprising the administration of fludarabine at or about 20-40 mg/m.sup.2 body surface area of the subject, optionally at or about 30 mg/m.sup.2, daily, for 2-4 days. In some of any embodiments, prior to the administration, the subject has received a lymphodepleting therapy comprising the administration of cyclophosphamide at or about 200-400 mg/m.sup.2 body surface area of the subject, optionally at or about 300 mg/m.sup.2, daily, for 2-4 days. In some of any embodiments, the subject has received a lymphodepleting therapy comprising the administration of fludarabine at or about 30 mg/m.sup.2 body surface area of the subject, daily, and cyclophosphamide at or about 300 mg/m.sup.2 body surface area of the subject, daily, each for 3 days.

[0060] In some of any embodiments, the method is capable of achieving a specified response or outcome, optionally at a designated timepoint following initiation of the administration, in at least one of or in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of subjects in a cohort of subjects having the MM, wherein: the response is selected from the group consisting of objective response (OR), complete response (CR), stringent complete response (sCR), very good partial response (VGPR), partial response (PR) and minimal response (MR); the response or outcome is or comprises an OR; and/or the response or outcome is or comprises a CR.

[0061] In some of any embodiments, the cohort of subjects has at least the same number of prior therapies, prognosis or prognostic factor, sub-type, secondary involvement or other specified patient characteristic or characteristics, as the subject treated by the method. In some of any embodiments, the response or outcome is durable for greater than at or about 3, 6, 9 or 12 months. In some of any embodiments, the response or outcome determined at or about 3, 6, 9 or 12 months after the designated timepoint is equal to or improved compared to the response or outcome determined at the designated timepoint.

[0062] In some of any embodiments, the response or outcome is or comprises or further comprises the absence of neurotoxicity, the absence of cytokine release syndrome (CRS), and/or the absence of macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH). In some of any embodiments, the method does not result in a specified toxicity outcome, optionally at a designated timepoint following initiation of the administration, in at least one of or in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM.

[0063] In some of any embodiments, the specified toxicity outcome is neurotoxicity, cytokine release syndrome (CRS), and/or macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH). In some of any embodiments, the specified toxicity outcome is neurotoxicity, and neurotoxicity does not result in at least 60%, 70% or 80% of the subjects in the cohort of subjects having the MM. In some of any embodiments, the specified toxicity outcome is grade 3 or higher, or grade 4 or higher, neurotoxicity. In some of any embodiments, the specified toxicity outcome is grade 3 or higher neurotoxicity, and grade 3 or higher neurotoxicity does not result in at least 80%, 85%, 90% or 95% of the subjects in the cohort of subjects having the MM. In some of any embodiments, the specified toxicity outcome is cytokine release syndrome (CRS), optionally grade 3 or higher, or grade 4 or higher, cytokine release syndrome (CRS). In some of any embodiments, the CRS does not result in at least 15%, 20%, 25% or 30% of the subjects in the cohort of subjects having the MM. In some of any embodiments, the designated timepoint is at or about or within 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 13 days, 14 days or 15 days following initiation of administration. In some of any embodiments, the designated timepoint is at or about 1 month, 3 months, 6 months, 9 months, or 12 months following initiation of the administration.

[0064] In some of any embodiments, the method does not result in any cytokine release syndrome (CRS) in at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In some of any embodiments, the method does not result in severe cytokine release syndrome (CRS) in at least at least at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In some of any embodiments, the method does not result in any neurotoxicity in at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In some of any embodiments, the method does not result in severe neurotoxicity in at least at least at least 70%, at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In some of any embodiments, the method does not result in severe CRS and severe neurotoxicity in at least at least at least 70%, at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In some of any embodiments, the method does not result in severe CRS and severe neurotoxicity in at least 80%, at least 90%, or at least 95% of subjects in the cohort of subjects having the MM. In any of such embodiment, the severe CRS is grade 3 or higher, grade 4 or higher or grade 5 CRS. In any of such embodiments, the severe neurotoxicity is grade 3 or higher, grade 4 or higher or grade 5 CRS.

[0065] In some of any embodiments, the administration of the composition is carried out on an outpatient basis, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic. In some of any embodiments, the administration of the composition is without admitting the subject to a hospital and/or without an overnight stay at a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic. In some of any embodiments, the administration of the composition is without requiring admission to or an overnight stay at a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic.

[0066] In some of any embodiments, the composition comprising engineered T cells is administered parenterally, optionally intravenously. In some of any embodiments, the subject is a human subject.

[0067] In some of any embodiments, the composition comprising engineered T cells is produced by a manufacturing process comprising: (i) exposing an input composition comprising primary T cells with a stimulatory reagent comprising an oligomeric particle reagent comprising a plurality of streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein: the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof; (ii) introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells; (iii) incubating the population of transformed cells for up to 96 hours; and (iv) harvesting T cells of the population of transformed cells, thereby producing a composition of engineered cells, wherein the harvesting is carried out at a time between 24 and 120 hours, inclusive, after the exposing to the stimulatory reagent is initiated. In some embodiments, the input composition autologous T cells selected from the subject, such as enriched by immunoaffinity-based selection for CD3 T cells or CD4 and CD8 T cells from a blood or apheresis (e.g. leukarephesis) sample from the subject.

[0068] In some of any embodiments, the composition may include engineered T cells is produced by a manufacturing process including exposing an input composition including primary T cells with a stimulatory reagent including an oligomeric particle reagent including a plurality of avidin, streptavidin, avidin mutein, or streptavidin mutein molecules under conditions to stimulate T cells, thereby generating a stimulated population, wherein the stimulatory reagent is capable of activating one or more intracellular signaling domains of one or more components of a TCR complex and one or more intracellular signaling domains of one or more costimulatory molecules. In some of any embodiments, the manufacturing process may further include introducing into T cells of the stimulated population, a heterologous polynucleotide encoding the CAR that targets BCMA, thereby generating a population of transformed cells. In some of any embodiments, the manufacturing process may further include incubating the population of transformed cells for up to 96 hours. In some of any embodiments, the incubating is carried out in basal media lacking one or more recombinant cytokines.

[0069] In some of any embodiments, the oligomeric particle reagent comprises a first agent comprising an anti-CD3 antibody or antigen binding fragment thereof and a second agent comprising an anti-CD28 antibody or antigen binding fragment thereof. In some of any embodiments, the anti-CD3 antibody or antigen binding fragment is a Fab and the anti-CD28 antibody or antigen binding fragment is a Fab. In some of any embodiments, the first agent and the second agent each comprise a streptavidin-binding peptide that reversibly binds the first agent and the second agent to the oligomeric particle reagent, optionally wherein the streptavidin-binding peptide comprises the sequence of amino acids set forth in any of SEQ ID NOS:266-270. In some of any embodiments, the streptavidin mutein molecule is a tetramer of a streptavidin mutein comprising amino acid residues Val44-Thr45-Ala46-Arg47 or Ile44-Gly45-Ala46-Arg47, optionally wherein the streptavidin mutein comprises the sequence set forth in any of SEQ ID NOS: 257, 272, 275, 277, 279, 273 or 276. In some of any embodiments, the oligomeric particle reagent comprises between 1,000 and 5,000 streptavidin mutein tetramers, inclusive. In some of any embodiments, the method further comprises, prior to harvesting the cells, adding biotin or a biotin analog after or during the incubation.

[0070] In some of any embodiments, the manufacturing process further includes harvesting T cells of the transformed population, thereby producing a composition of engineered cells. In some of any embodiments, the harvesting is carried out at a time between 24 and 120 hours, inclusive, after the exposing to the stimulatory reagent is initiated. In some of any embodiments, the harvesting is carried out at a time between 48 and 120 hours, inclusive, after the exposing to the stimulatory reagent is initiated. In some of any embodiments, the harvesting is carried out at a time when integrated vector is detected in the genome but prior to achieving a stable integrated vector copy number (iVCN) per diploid genome. In some of any embodiments, the harvesting is carried out at a time before the total number of viable cells at the harvesting is more than or more than about three times as the number of total viable cells of the stimulated population. In some of any embodiments, the harvesting is carried out at a time when the total number of viable cells at the harvesting is at or about three times, at or about two times, or the same or about the same as the number of total viable cells of the stimulated population. In some of any embodiments, the harvesting is carried out at a time when the percentage of CD27.sup.+CCR7.sup.+ cells is greater than or greater than about 50% among total T cells in the population, total CD3.sup.+ T cells in the population, total CD4.sup.+ T cells in the population, or total CD8.sup.+ T cells, or of CAR-expressing cells thereof, in the population. In some of any embodiments, the harvesting is carried out at a time when the percentage of CD45RA.sup.+CCR7.sup.+ and CD45RA.sup.−CCR7.sup.+ cells is greater than or greater than about 60% among total T cells in the population, total CD3.sup.+ T cells in the population, total CD4.sup.+ T cells in the population, or total CD8.sup.+ T cells, or of CAR-expressing cells thereof, in the population.

[0071] In some of any embodiments, the cells in the administered composition are produced by a manufacturing process to produce an output composition exhibiting a predetermined feature, wherein iterations of the manufacturing process produce a plurality of the output compositions, optionally from human biological samples, when carried out among a plurality of different individual subjects, in which the predetermined feature of the output composition among the plurality of output compositions is selected from the mean percentage of cells of a memory phenotype in the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; the mean percentage of cells of a central memory phenotype in the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; the mean percentage of cells that are CD27+, CD28+, CCR7+, CD45RA−, CD45RO+, CD62L+, CD3+, CD95+, granzyme B−, and/or CD127+ in the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; the mean percentage of cells that are CCR7+/CD45RA− or CCR7+/CD45RO+ in the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; the mean percentage of central memory CD4+ T cells in the engineered CD4+ T cells, optionally CAR+CD4+ T cells, of the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; the mean percentage of central memory CD8+ T cells in the engineered CD8+ T cells, optionally CAR+CD8+ T cells, of the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%; and/or the mean percentage of central memory T cells, optionally CD4+ central memory T cells and CD8+ central memory T cells, in the engineered T cells, optionally CAR+ T cells, of the plurality of the output compositions is between about 40% and about 65%, between about 40% and about 45%, between about 45% and about 50%, between about 50% and about 55%, between about 55% and about 60%, or between about 60% and about 65%.

[0072] In some of any embodiments, the administered composition is produced by a manufacturing process to produce an output composition exhibiting a predetermined feature, optionally a threshold number of cells expressing the CAR in the output composition, in at least about 80%, about 90%, about 95%, about 97%, about 99%, about 100%, or is 100% of the human biological samples in which it is carried out among a plurality of different individual subjects. In some of any embodiments, the composition including genetically engineered cells does not contain residual beads from the manufacturing process.

[0073] In some of any embodiments, the MM is a relapsed and/or refractory multiple myeloma (r/r MM).

[0074] Also provided herein is an article of manufacture including a composition including genetically engineered cells expressing a chimeric antigen receptor (CAR) that targets BCMA, and instructions for administering the composition of the cells in accordance with the method of any of the methods provided herein.



     e-mail to a friend      printer-friendly     add to library      
|  
Recs: 0  
   Views: 0 []
Previous Message  Next Message    Post Message    Post a Reply return to message boardtop of board




Financial Market Data provided by
.
Loading...