Discovery of BMS-986408, a First-In-Class Dual DGK⍺ and DGK𝛇 Inhibitor That Unleashes PD-1 Checkpoint and CAR-T Cell Immunotherapies

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 disclose the discovery and pre-clinical characterization of the first 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 DAG-substrate competitive inhibition, subcellular translocation to 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 uniquely amplifying the priming and expansion of tumor-reactive T cells in the tumor-draining lymph nodes. Importantly, simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. DGKα and DGKζ were broadly expressed in NSCLC 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 the first critical step towards evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in cancer patients. MC38 tumors were injected into female C57BL/6 mice and grown to a mean tumor volume of ~100 mm3. Animals were then randomized into anti-PD1, BMS-986408, combination anti-PD1/BMS-986408, or vehicle isotype control arms (n = 5 per arm) and tumors were collected seven days after the initiation of treatment. We generated bulk RNA sequencing libraries to profile gene expression changes induced by each treatment and differential expression analysis was performed between different treatment arms.