Inhibition of Caspase-1 Improves CAR T-Cell Safety, Efficacy

Caspase-1 inhibition with VX765 significantly reduced chimeric antigen receptor (CAR) T-cell apoptosis, improved memory phenotype, and boosted delayed proliferation of CAR T-cells, according to Wannankorn Khopanlert, MD, of the Mayo Clinic, in a presentation at the 66^th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The study was motivated by previous data that concluded sequential therapy with tafasitamab, an anti-CD19 monoclonal antibody, and CD19-directed CAR T-cells led to “significantly ameliorated CAR T-cell apoptosis and tumor cell proptosis, improving CAR T-cell therapy safety and efficacy.”

To test their hypothesis, Dr. Khopanlert and colleagues evaluated caspase-1, caspase-3, caspase-7, and caspase-11 inhibitors in combination with CAR T-cells. VX765 had no impact on CAR T-cell antigen-specific cytotoxicity and was further investigated in the JeKo-1 mantle cell lymphoma line.

In testing, CAR T-cells had higher proliferation at day five with VX765 present compared to a control (P=.03) based on absolute CD3-positive cell counts on flow cytometry. Further co-culturing showed a significant reduction in apoptotic CAR T-cells with VX765 (P=.05). In addition, the authors reported significantly reduced pyroptosis (P=.02) with higher apoptosis in VX765-treated cultures (P=.04)

In a murine lymphoma cell line, mice treated with VX765 maintained weight and showed no signs of cytokine release syndrome (CRS) compared to vehicle control. Overall, VX765-treated mice showed sustained CAR T-cell persistence with anti-tumor activity.

“Given the favorable preclinical outcomes and existing clinical data on VX765,” the authors stated, “this approach holds substantial translational potential for enhancing the safety and efficacy of CAR T-cell therapy in patients with large B-cell lymphoma.”

Reference

Khopanler W, Huynh T, Kimball BL, et al. Caspase-1 inhibition ameliorates CAR T-cell apoptosis and tumor cell pyroptosis to enhance the efficacy and safety of CAR T-cell therapy. Abstract #907. Presented at the 66th American Society of Hematology Annual Meeting & Exposition. December 7-10, 2024; San Diego, California.