Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma.

Autor:	Tang B; Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois., Guo ZS; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Bartlett DL; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Yan DZ; Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois., Schane CP; Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois., Thomas DL; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio., Liu J; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas., McFadden G; Biodesign Institute, Arizona State University, Tempe, Arizona., Shisler JL; Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois., Roy EJ; Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois. eroy@illinois.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 May 01; Vol. 26 (9), pp. 2216-2230. Date of Electronic Publication: 2020 Feb 04.
DOI:	10.1158/1078-0432.CCR-18-3626
Abstrakt:	Purpose: We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells. Experimental Design: Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15Rα-IL15 and a fluorescent protein. Viral gene expression (YFP or tdTomato Red) was confirmed in the murine glioma GL261 in vitro and in vivo . GL261 tumors in immunocompetent C57BL/6J mice were treated with vvDD-IL15Rα-YFP vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T-cell therapy. Results: vvDD-IL15Rα-YFP and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro . In vivo , NK cells and CD8 + T cells were increased in the tumor due to the expression of IL15Rα-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15Rα-IL15 expressed by the virus, a source of T cells (whether by prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDD-IL15Rα-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice. Conclusions: IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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