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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE293295 | GEO | 2025/04/04

REPOSITORIES: GEO

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Project description:Purpose Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for individual non-small-cell lung cancer (NSCLC) patients. Most current molecular signatures for lung cancer are prognostic only and provide limited information with regard to the functional importance of the genes selected. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefit of ACT in NSCLC. Experimental Design An 18-hub-gene prognosis signature was developed through a systems biology approach using a large NSCLC dataset from the Director’s Challenge Consortium. The prognostic value of this signature was tested in NSCLC patients from UT Lung SPORE cohort and additional five public datasets. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefit in NSCLC. Results We showed that the 18-hub-gene set can robustly predict the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The refined 12-gene functional set was successfully validated in two independent datasets. The predicted benefit group showed significant improvement in survival after ACT (JBR.10 clinical trial data: hazard ratio=0.36, p=0.038; UT Lung SPORE data: hazard ratio=0.34, p=0.017), while the predicted non-benefit group showed no survival improvement. Conclusions This is the first study to integrate genetic aberration, genome-wide RNAi functional data, and mRNA expression data to identify a functional gene set that is predictive for ACT benefits. This 12-gene predictive signature has been validated in two independent NSCLC cohorts. Patients were eligible to enter the study if they underwent curative resection for NSCLC at MD Anderson Cancer Center between December 1996 and June 2007, and patients with radiation therapy were excluded from the study. All tissue samples were obtained by surgical resection from patients who had provided written informed consent. Tissues were stored at −140°C after being snap frozen in liquid nitrogen. Serial sectioning of each sample was used to histologically evaluate tumor and malignant cells content before RNA extraction. The primary tumor tissues from 176 patients were selected randomly from similar samples in the UT Lung SPORE tumor collection based on stringent, predefined quality control procedures before any data analysis, including the presence of ≥70% tumor tissue and ≥50% malignant cells in the frozen tissue used for RNA extraction. In this cohort, 133 patients are adenocarcinomas (ADCs) and 43 patients are squamous cell carcinomas (SCCs); 49 patients received ACT (mainly Carboplatin plus Taxanes) and 127 patients did not receive ACT.

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

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