Enhanced anti-tumor efficacy through combined CAR T cell therapy and CD40 stimulation in syngeneic solid tumor models

Background Solid tumors present unique barriers to treatment with CAR T cells, including poor tumor infiltration into a highly immunosuppressive and metabolically challenging tumor microenvironment (TME). Objectives To enhance both CAR T cell efficacy and the overall immune response against solid tumors, this study explored the therapeutic potential of combining chimeric antigen receptor (CAR) T cells with CD40 stimulation via an agonistic CD40 antibody (αCD40). We hypothesized that CAR T cells could serve as targeted vaccines, promoting antigen release and cooperating with αCD40 to activate and mobilize the endogenous immune cells, thus "heating up" the TME and potentially rendering it more receptive to subsequent therapies. Methods We used a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC) and further validated our findings in a triple-negative breast cancer (TNBC) mouse model Results This combined strategy was associated with enhanced anti-tumor activity over CAR T cells alone. This included rapid and sustained tumor necrosis, increased immune cell activation both systemically and within the TME, as well as an overall improvement in survival rates. Comprehensive immune profiling at early timepoints revealed mechanistic insights into the enhanced anti-tumor effects of CAR T cell therapy and αCD40 treatment. Conclusions These findings set the stage for future clinical applications of CAR T cells in combination with CD40 agonists for the treatment of challenging solid tumors.