Triple checkpoint blockade, but not anti-PD-1 alone, enhances engineered adoptive T cell therapy in a mouse model of advanced ovarian cancer 2090

Abstract Description The 5-year survival rate for ovarian cancer (OvCA) patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (Msln) contributes to the invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in an OvCA mouse model demonstrated that T cells engineered to express a T cell receptor targeting Msln (TCRMsln) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function in the TME and improve therapeutic efficacy, but administration of mono-specific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3 and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCRMsln with singlet or doublet antibody combinations. These results suggest strategies to disrupt multiple inhibitory pathways may be necessary for efficacy in OvCA. Funding Sources Supported by 2T32CA009657-26A1, 1K22CA266737-01A1, CA018029, CA033084, an OCRA Mentored Investigator Training Grant, STTR Award, and the Emerson Collective; research agreements with the Parker Inst., Lonza, and Juno Therapeutics. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)