Overcoming Resistance to Immune Checkpoint Inhibitors with Oncolytic Viruses

ESMED General Assembly 2022, Madrid Spain

Immune checkpoint inhibitors (ICIs) that block the T cell suppressing activity of immune checkpoint proteins including CTLA-4, PD-1/PD-L1 and LAG-3 have revolutionized the practice of oncology and are translating into marked increases in progression-free survival (PFS) as well as overall survival (OS) in multiple cancer types. Unfortunately, intrinsic and acquired resistance to ICIs is common in the majority of cancer patients. Multiple strategies to overcome ICI resistance have been proposed including promoting T cell priming and infiltration and inhibiting T cell exhaustion and the immunosuppressive microenvironment. Oncolytic viruses that selectively replicate within and lyse cancer cells cause antigen release and activate innate immune responses which, in turn, may lead to both T cell priming and infiltration. Accordingly, the combined administration of ICIs with oncolytic viruses may overcome resistance and increase PFS and OS in multiple cancer types. The first oncolytic virus to receive FDA-approval, talimogene laherparepvec (TVEC), is an attenuated herpes simplex virus, type 1, engineered to express granulocyte-macrophage colony stimulating factor which stimulates the generation of antigen-presenting dendritic cells and T cell priming. In randomized clinical trials, this first-in-class oncolytic virus was found to increase the efficacies of ICIs that target CTLA-4 (ipilimumab) and PD1 (pembrolizumab) and a recent phase 2 clinical trial reported that TVEC can overcome resistance to pembrolizumab in melanoma patients. Based on these data, intratumoral injection of TVEC may prove to have utility to overcome resistance to ICIs and thus warrants further investigation.