Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma.

ABSTRACT: 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 IL15R?-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 IL15R?-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-IL15R?-YFP vaccinia virus or vMyx-IL15R?-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T-cell therapy.

Results: vvDD-IL15R?-YFP and vMyx-IL15R?-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 IL15R?-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15R?-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-IL15R?-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15R?-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice.

Conclusions: IL15R?-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib.

SUBMITTER: Tang B 

PROVIDER: S-EPMC7723446 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature