Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma

Bingtao Tang, Zong Sheng Guo, David L. Bartlett, David Z. Yan, Claire P. Schane, Diana L. Thomas, Jia Liu, Grant McFadden, Joanna L. Shisler, Edward J. Roy, Edward J. Roy

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Purpose: We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an antiimmunosuppressant 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. vvDDIL15Rα- 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.

Original languageEnglish (US)
Pages (from-to)2216-2230
Number of pages15
JournalClinical Cancer Research
Volume26
Issue number9
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tang, B., Guo, Z. S., Bartlett, D. L., Yan, D. Z., Schane, C. P., Thomas, D. L., Liu, J., McFadden, G., Shisler, J. L., Roy, E. J., & Roy, E. J. (2020). Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma. Clinical Cancer Research, 26(9), 2216-2230. https://doi.org/10.1158/1078-0432.CCR-18-3626