Oncolytic viral immunotherapy is a novel approach to cancer treatment. Viruses can directly kill cancer cells, provide antigens to dendritic cells to stimulate a T cell response, and make cancer cells express genes of immune-enhancing cytokines locally within the tumor microenvironment. We hypothesized that the combination of oncolytic virus with a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas and applying the combination treatment after the resection of late-stage established glioma might overcome immunosuppression caused by surgical trauma, kill the residual tumor and cure glioma-bearing mice. 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. 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. The feasibility of partial resection of late-stage established glioma in mouse brain was confirmed. We found that 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 pre-vaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDD-IL15Rα-YFP occasionally caused encephalitis, 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 All these facts suggest that IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T cell therapy, rapamycin and celecoxib. And it is possible to do tumor resection on mice bearing late-stage glioma. We are working on applying the combination treatment after the resection of late-stage established glioma. Citation Format: Bingtao Tang, Zong Sheng Guo, David Bartlett, Jia Liu, Grant McFadden, Joanna Shisler, Kari Foss, Heidi Phillips, Terence Lichtor, Edward Roy. Synergistic combination of oncolytic virotherapy and immunotherapy for glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 912.