ITOC2 – 010. Virotherapy overcomes tumour resistance to PD1-immunotherapy by broad mutanome-directed T cell responses

Preexisting antitumoural T cell responses appear to be a precondition for effective PD1 immunotherapy, but concomitant cancer vaccinations did not affect the clinical outcome. We investigated whether oncolytic virotherapy (OV) is capable to overcome resistance to PD1-immunotherapy. To analyse antitumoural T cell responses, we performed transcriptome sequencing of PD1-resistant murine CMT64 cells and screened for putative neoepitopes in mutated genes using an MHC class I epitope prediction algorithm. Neoepitopes were then analysed by ELISpot analysis. Furthermore, induction of cytotoxic responses were confirmed by in vivo cytotoxic assays. Mutanome-specific T cells were detected by pentamers. PD1 immunotherapy was capable of inducing a single neoepitope-specific response, whereas OV elicited cytotoxic T cell responses to a conserved set of 5–7 neoepitopes. Unexpectedly, OV-induced antitumoural responses were not enhanced by subsequent PD1 blockade. Instead, we observed a broadening of T cell responses to additional neoepitopes of the mutanome. OV of the primary tumour abrogated tumour-specific resistance to PD1 immunotherapy as shown by improved elimination of disseminated lung colonies. Our observation was additionally confirmed in a transgenic cholangiocarcinoma model, where this approach completely eliminated lung metastasis. Our results strongly recommend viral oncolysis and concomitant PD1 immunotherapy for further evaluation in clinical studies.