Wichroski and Liu et al. developed BMS-986408, a potent dual DGKα/ζ inhibitor that binds to the accessory subdomain of the catalytic domain, and inhibits DGKα/ζ through the competitive substrate inhibition, subcellular translocation, and proteasomal degradation. BMS-986408 amplified the priming and expansion of tumor-reactive T cells in the TdLN and improved the therapeutic efficacy of PD-1 in syngeneic tumors and NSCLC PDOTs. Inhibition of both DGKα and DGKζ isozymes was required to potentiate TCR signaling and activation. BMS-986408 also improved CAR T cell therapy efficacy, overcoming hallmarks of poor CAR T cell responses.
Contributed by Shishir Pant
ABSTRACT: Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol (DAG) metabolism, making them attractive targets for next-generation immunotherapy. Here, we report the discovery and pre-clinical characterization of the clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes competitive inhibition for the DAG substrate, subcellular translocation to the plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T-cell responses in the tumor while also amplifying the priming and expansion of tumor-reactive T cells in the tumor-draining lymph nodes. Simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. Further, we observed in non-small cell lung cancer (NSCLC) patient samples that DGKα and DGKζ were broadly expressed in tumor-infiltrated T cells and combination therapy invigorated a robust cytokine response in NSCLC patient-derived organotypic tumors supporting the clinical evaluation of this combination in NSCLC patients. BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypo-functionality, insufficient expansion, and lack of co-stimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in cancer patients.
Author Info: (1) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (2) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (3) Dana-Farber Cancer Institute, Bo
Author Info: (1) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (2) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (3) Dana-Farber Cancer Institute, Boston, MASSACHUSETTS, United States. (4) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (5) Brigham and Women's Hospital, Boston, MA, United States. (6) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (7) Bristol-Myers Squibb (United States), Brisbane, CA, United States. (8) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (9) Bristol-Myers Squibb (United States), Seattle, WA, United States. (10) Bristol-Myers Squibb (United States), Seattle, WA, United States. (11) Dana-Farber Cancer Institute, Boston, United States. (12) Dana-Farber Cancer Institute, Boston, MA, United States. (13) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (14) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (15) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (16) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (17) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (18) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (19) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (20) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (21) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (22) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (23) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (24) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (25) Bristol-Myers Squibb (United States), United States. (26) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (27) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (28) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (29) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (30) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (31) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (32) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (33) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (34) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (35) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (36) Dunad Therapeutics, Boston, MA, United States. (37) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (38) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (39) Bristol-Myers Squibb (United States), Lawrence Twp, NJ, United States. (40) Bristol-Myers Squibb (United States), Seattle, WA, United States. (41) Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States. (42) Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. (43) Brigham and Women's Hospital, Boston, MA, United States. (44) Bristol-Myers Squibb (United States), United States. (45) Bristol-Myers Squibb (United States), Cambridge, MA, United States. (46) Dana-Farber Cancer Institute, Boston, MA, United States. (47) Dana-Farber Cancer Institute, Boston, Massachusetts, United States. (48) Dana-Farber Cancer Institute, Boston, MA, United States. (49) Bristol-Myers Squibb (United States), Cambridge, CA, United States.
