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

Guan Wang,Xue F Huang,Lindsey Jones,Jie Chen,Xi Kang,Katherine S Chen,Tiffany Jehng,Si-Yi Chen

doi:10.1038/s41467-020-15229-5

Guan Wang, Xue F Huang + Show 6 more

Open Access

https://doi.org/10.1038/s41467-020-15229-5

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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. 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.

Highlights

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses
We generate an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) that coexpresses a PD-L1 inhibitor and GMCSF. We find that this engineered oncolytic virus is capable of activating neoantigen-specific T cell responses by the likely synergistic action of viral replication, granulocytemacrophage colony-stimulating factor (GM-CSF) stimulation, and PD-L1 inhibition on tumor cells and immune cells, providing a novel oncolytic immunotherapy
We generated an engineered oncolytic VV coexpressing a murine soluble PD-1 extracellular domain fused with IgG1 Fc as a PD-L1 inhibitor and murine GM-CSF (VV-iPDL1/GM), in the backbone of a tumor-selective double-deleted oncolytic VV, in which thymidine kinase (TK) and vaccinia growth factor viral genes had been deleted[25,26,27,28,29] (Fig. 1a)

Summary

Introduction

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. 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 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. We generate an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) that coexpresses a PD-L1 inhibitor and GMCSF We find that this engineered oncolytic virus is capable of activating neoantigen-specific T cell responses by the likely synergistic action of viral replication, GM-CSF stimulation, and PD-L1 inhibition on tumor cells and immune cells, providing a novel oncolytic immunotherapy

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Conclusion