Immunotherapy for murine glioma

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. An oncolytic virus encoding IL15Ra-IL15 (the T cell activating stimulus) and the prostaglandin synthesis inhibitor celecoxib (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 IL15Ra-IL15 and a fluorescent protein (YFP or tdTomato Red). Viral gene expression (YFP or tdTomato Red) was confirmed in the murine glioma line GL261 in vitro and in vivo. Orthotopic GL261 tumors in immunocompetent C57BL/6J mice were treated with vvDD-IL15Ra-YFP vaccinia virus or vMyx-IL15Ra-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T cell therapy. We found that vvDD-IL15Ra-YFP and vMyx-IL15Ra-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 IL15Ra-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15Ra-IL15 expressed by the virus, a source of T cells (whether by pre-vaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce total elimination of gliomas in a majority of mice gliomas. vvDD-IL15Ra-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15Ra-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 IL15Ra-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T cell therapy, rapamycin and celecoxib and that this combination treatment might be a promising method for human glioma therapy.U of I OnlyAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD syste