Discovery of BMS-986408, a First-In-Class Dual DGKα and DGKζ Inhibitor that Unleashes PD-1 Checkpoint and CAR T-cell Immunotherapies.

Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol metabolism, making them attractive targets for next-generation immunotherapy. In this study, we report the discovery and preclinical 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 diacylglycerol 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 tumor-draining lymph nodes. Simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. Furthermore, we observed in non-small cell lung cancer (NSCLC) patient samples that DGKα and DGKζ were broadly expressed in tumor-infiltrated T cells and that combination therapy invigorated a robust cytokine response in organotypic tumors derived from patients with NSCLC, supporting the clinical evaluation of this combination in patients with NSCLC. BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypofunctionality, insufficient expansion, and lack of costimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in patients with cancer.