Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

• Published in: Nature communications Vol. 11; no. 1; pp. 524 - 15
• Main Authors: Mosaheb, Mubeen M., Dobrikova, Elena Y., Brown, Michael C., Yang, Yuanfan, Cable, Jana, Okada, Hideho, Nair, Smita K., Bigner, Darell D., Ashley, David M., Gromeier, Matthias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 13/51; 631/250/251; 631/326/596; 631/67/1059/4042; 631/67/1858; 692/4028/67/1922; Adaptive immunity; Animal models; Animals; Antigen (tumor-associated); Antigen presentation; Antigens; Cancer Vaccines; CD8 antigen; CD8-Positive T-Lymphocytes - physiology; Cell adhesion & migration; Cell migration; Chimeras; Cytokines; Dendritic cells; Dendritic Cells - immunology; Epitopes; Expression vectors; Genetic Vectors - immunology; Genomic instability; Glioblastoma; Glioma - immunology; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Immunity; Immunity, Innate; Immunotherapy - methods; Innate immunity; Inoculation; Interferon Type I - immunology; Lymphocytes; Lymphocytes T; Melanoma - immunology; Mice; Mice, Inbred C57BL; multidisciplinary; Oncolysis; Poliovirus - genetics; Poliovirus - immunology; Priming; Science; Science (multidisciplinary); Survival; Tropism; Tumors; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13939-z

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models. Experimental PVSRIPO oncolytic virus therapy of glioblastoma has shown long-term efficacy in a subset of patients. Here the authors engineer the virus to enable incorporation of tumor-specific antigens, and show proof-of-principle evidence that this modification increases anti-tumor immunity and extends survival in mice.