Provided are inhibitors of diacylglycerol kinases (DGK) and methods for treating diseases that would benefit from the stimulation of the immune system, such as cancer and infections diseases, comprising administering a DGK inhibitor in combination with an antagonist of the PD 1/PD-L 1 axis and/or an antagonist of CTLA4.

CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 62/950,570 filed Dec. 19, 2019, which is incorporated herein in its entirety.

BACKGROUND

[0002] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. However, although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as “self” and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively subvert anti-tumor immunity. These mechanisms include dysfunctional T-cell signaling (Mizoguchi et al., (1992) Science 258:1795-98), suppressive regulatory cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and the co-opting of endogenous “immune checkpoints”, which serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-489).

[0003] Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T cell functions propagated through the TCR signaling pathway. Thus, DGKs serve as intracellular checkpoints and inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation. Supporting evidence include knock-out mouse models of either DGKa or DGKζ which show a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese M. J. et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock B. A. et al., (2006) 11: 1174-81). Furthermore tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients were observed to overexpress DGKa which resulted in inhibited T cell function (Prinz, P. U. et al., J Immunology (2012) 12:5990-6000). Thus, DGKa and DGKζ are viewed as targets for cancer immunotherapy (Riese M. J. et al., Front Cell Dev Biol. (2016) 4: 108; Chen, S. S. et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686.

SUMMARY

[0004] Provided herein are methods of treating a disease or disorder comprising administering to a subject an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 or a pharmaceutically acceptable salt thereof in combination with an antagonist of the PD1/PD-L1 axis and/or an antagonist of CTLA4. Exemplary diseases or disorders include those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases. Also provided are uses of an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the inhibitor is administered in combination with an antagonist of the PD1/PD-L1 axis and/or an antagonist of CTLA4. Provided herein are uses of an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the inhibitor is administered in combination with an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA4.

[0005] Also provided are uses of an antagonist of the PD1/PD-L1 axis, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the antagonist is administered in combination with an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof and/or an antagonist of CTLA4. Provided are uses of an antagonist of the PD1/PD-L1 axis, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the antagonist is administered in combination with an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof and an antagonist of CTLA4.

[0006] Also provided are uses of an antagonist of CTLA4, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the antagonist is administered in combination with an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof and/or an antagonist of the PD1/PD-L1 axis. Provided are uses of an antagonist of CTLA4, for the manufacture of a medicament for the treatment of diseases or disorders, such as those that would benefit from the stimulation of the immune system, such as cancer and infectious diseases, and wherein the antagonist is administered in combination with an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof and an antagonist of the PD1/PD-L1 axis.

[0007] Exemplary compounds, such as compounds of Formula I described herein and pharmaceutically acceptable salts thereof, are described in PCT/US2019/039131, filed Jun. 26, 2019, and PCT/US2019/039135, filed Jun. 26, 2019, the contents of both of which are specifically incorporated by reference herein. Exemplary compounds, such as compounds of Formula II described herein and pharmaceutically acceptable salts thereof, are described in PCT/US2020/048070, filed Aug. 27, 2020, the contents of which are specifically incorporated by reference herein.

[0008] These and other features of the new methods of treatments will be set forth in expanded form as the disclosure continues.