Boosting anti-tumor immunity with TILT-517 oncolytic adenovirus and checkpoint blockade in renal cell carcinoma

Elevated levels of immune infiltration found in renal cell carcinoma are often associated with poor patient prognosis, likely due to T cell exhaustion and an immunosuppressive tumor microenvironment, which limits the efficacy of current immunotherapies. In this study, we focused on the use of Ad5/3-E2F-d24-hIL7 (TILT-517), an oncolytic adenovirus expressing interleukin-7, as a strategy to selectively lyse tumors. This approach also seeks to activate infiltrating immune cells, thereby reprogramming the immune landscape characteristic of renal cell carcinoma tumors. Furthermore, we evaluated the combination of TILT-517 with immune checkpoint inhibitors, main immunotherapeutic component for this disease. Anti-tumor efficacy was significantly observed in <i>ex vivo</i> patient-derived tumors when treated with TILT-517 in monotherapy and in treatment combination. Cellular and proteomic changes were detected in the tumor microenvironment, including enhanced cytotoxicity of effector populations such as CD4⁺, CD8⁺ T cells, natural killer, and natural killer T cells. <i>In vivo</i>, we developed a novel syngeneic Syrian hamster model for renal cancer, and TILT-517+anti-PD-L1 group presented significant enhanced tumor growth control and led to an increased number of effector and antigen-presenting cells compared to anti-PD-L1 monotherapy. Hence, TILT-517 offers a promising approach for renal cell carcinoma treatment, boosting therapeutic efficacy and reshaping the tumor microenvironment.