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

Guan Wang, Xi Kang, Katherine S. Chen, Tiffany Jehng, Lindsey Jones, Jie Chen, Xue F. Huang () and Si-Yi Chen ()
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Guan Wang: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Xi Kang: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Katherine S. Chen: Fu Foundation School of Engineering and Applied Science, Columbia University
Tiffany Jehng: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Lindsey Jones: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Jie Chen: Pomona Biotechnology Corp.
Xue F. Huang: Pomona Biotechnology Corp.
Si-Yi Chen: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15229-5

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