Cancer immunotherapy with oncolytic enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways

Abstract

Abstract Tumors are adept at escaping the immune response through multiple mechanisms that disrupt key processes. This is observed with immune checkpoint blockade therapies and oncolytic viral therapies that are only effective in limited numbers of cancer patients. Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here we describe the use of virus-like vesicles (VLV) for the delivery of trivalent combination cancer therapy. This high-capacity oncolytic RNA replicon vector was adapted to simultaneously and synergistically stimulate immune cell activation, inhibit an immune checkpoint pathway, and disrupt a pro-tumor pathway by co-delivering interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA), respectively. This trivalent viral vector (designated CARG-2020) was injected intralesionally to subcutaneous MC38 and BNL-T3 tumors, and it eradicated large established tumors in mice. The concurrent modulation of IL-12, IL-17, and PD-L1 pathways by CARG-2020 suppressed tumor recurrence and prolonged overall survival. Treatment of primary tumors by CARG-2020 also resulted in marked inhibition of distal tumors, demonstrating a strong abscopal effect of the agent. Mechanistically, CARG-2020 potently activates Th1-armed immunity in primary tumors and the spleen, and inhibits the expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence in mice and extending their survival makes it a promising candidate for use in human cancer immunotherapy. This work is supported by a National Institute of Health/National Cancer Institute grant (NIH/NCI R01CA262430).