An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses

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. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, 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. In summary, this engineered oncolytic virus is able to activate 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.
Oncolytic viruses can activate tumor neoantigen-specific T cell responses. However, PD-L1 upregulation on tumor cells and immune cells leads to tumor resistance to this immunotherapy approach. Here, the authors develop an oncolytic virus which expresses both a PD-L1 inhibitor and GM-CSF which allows an improved tumor neoantigen-specific T cell response in preclinical models.