Combining CAR-T cells and Oncolytic Viruses for Cancer Immunotherapy

Abstract

INTRODUCTION: Immunotherapy continues to garner strong support for use in the treatment of cancer. Adoptive transfer therapies offer a promising approach to combating metastatic disease. In addition, viruses can also be exploited to drive antitumor immunity and tumor destruction. While the use of chimeric antigen receptor (CAR)-engineered T cells has shown dramatic clinical benefit for use in blood-based cancers, solid tumors remain a significant hurdle. METHODS: We have investigated the use of multi-faceted immunotherapies combining CAR-T cells with oncolytic virotherapy. We have also evaluated how these therapies interact with pre-conditioning lymphodepletion regimes. RESULTS: In chapter 3, we investigated the differences between three similar chimeric receptors targeting NKG2DL. Upon adoptive transfer, we observed dramatic T cell-induced toxicity. In addition, there were stark differences in the severity of toxicity induced between different receptors or across different mouse strains, or if combined with pre-conditioning chemotherapy. In chapter 4, we tested the ability of oncolytic vaccines to boost engineered T cells through their natural antigen receptor. While CAR-T cells could be boosted via oncolytic vaccines, prolonged T cell engraftment and successful oncolytic vaccine boost required pre-conditioning chemotherapy. Further analysis revealed a lack of antitumor function of the CAR-T cells in vivo. iii In chapter 5, we evaluated loading CAR-T cells with oncolytic viruses (OVs). Loading of CAR-T cells with OV did not impair CAR expression or functionality of the T cells. In addition, CAR target recognition did not impact the ability of OV-loaded cells to deposit OVs onto tumor targets. CAR-T cells loaded with OV also displayed enhanced antitumor functions as compared to either treatment alone. CONCLUSIONS: The research described in this thesis reveals important information into the interactions between CAR-T cells and OVs, and how pre- conditioning regimes may influence responses from either or both therapies. Overall, our research offers novel insight into future CAR-T cell therapeutic developments.