Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Less than 50% of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting need for novel therapies. A promising strategy employs T cells engineered to target tumor-expressed proteins. Mesothelin (Msln) is overexpressed cancers, contributes malignant and invasive phenotype limited expression healthy cells, making it a candidate immunotherapy target. We used immune-competent ID8 VEGFmouse model advanced show that express Msln-specific cell receptor (TCR Msln) can preferentially accumulate within established tumors, delay tumor growth significantly prolong mouse survival. However, elements microenvironment function. Tumor-bearing mice were therefore treated with TCR MslnT plus PD1, Tim-3 and/or Lag-3 checkpoint-blocking antibodies, alone or combination. Triple checkpoint blockade, but not single- double-agent treatments, dramatically increased effector cytokine production by intratumoral cells. Single RNA-sequencing revealed gene changes myeloid consistent immune activation inflammation. Moreover, combining adoptive triple blockade prolonged survival mice, relative Mslnwith without blockade. These results suggest disrupting multiple immune-inhibitory pathways simultaneously, which be more safely pursued intrinsic form through genetic engineering, may necessary improve outcomes patients.