Engineered oncolytic viruses expressing pd-l1 inhibitors and uses thereof

Abstract

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. Herein, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. This oncolytic virus is capable of secreting the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. The intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. This engineered oncolytic virus allows for activation of tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.

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