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

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling via diacylglycerol (DAG) metabolism.
• These kinases are attractive targets for developing novel immunotherapies.

Purpose of the Study:

• To discover and pre-clinically characterize BMS-986408, a novel inhibitor targeting DGKα and DGKζ.
• To evaluate the efficacy of BMS-986408 in combination with PD-1 therapy and CAR T-cell therapy.

Main Methods:

• Characterization of BMS-986408's mechanism of action, including substrate inhibition, subcellular translocation, and proteasome-dependent degradation.
• Assessment of combination therapy benefits in preclinical cancer models, including non-small cell lung cancer (NSCLC) patient samples and CD19-targeted CAR T-cell therapy.

Main Results:

• BMS-986408 inhibits DGKα/ζ through competitive DAG inhibition, translocation, and degradation.
• DGKα/ζ inhibition significantly enhanced PD-1 therapy by improving T-cell responses in tumors and lymph nodes.
• Simultaneous inhibition of both DGKα and DGKζ was crucial for maximizing combination benefits.
• BMS-986408 improved CAR T-cell therapy efficacy by overcoming hypo-functionality and enhancing expansion.
• NSCLC patient samples showed broad DGKα/ζ expression, and combination therapy induced robust cytokine responses.

Conclusions:

• BMS-986408 is a potent DGKα/ζ inhibitor with significant preclinical efficacy in combination with PD-1 and CAR T-cell therapies.
• Dual DGKα/ζ inhibition is necessary to maximize therapeutic benefits in immunotherapy.
• The findings support the clinical evaluation of BMS-986408 in NSCLC patients and other cancer types.