Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma
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 co...
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Published in | Clinical cancer research Vol. 26; no. 9; pp. 2216 - 2230 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.05.2020
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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
and
. 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.
vvDD-IL15Rα-YFP and vMyx-IL15Rα-tdTr each infected and killed GL261 cells
.
, 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.
IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib. |
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Bibliography: | Authors’ Contributions Writing, review, and/or revision of the manuscript: B. Tang, D.L. Bartlett, D.Z. Yan, C.P. Schane, D.L. Thomas, J. Liu, G. McFadden, E.J. Roy Study supervision: E.J. Roy Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D.L. Bartlett, J. Liu Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): B. Tang, D.L. Thomas, E.J. Roy Other (supplied stocks of virus needed for study): G. McFadden Conception and design: B. Tang, Z.S. Guo, D.L. Bartlett, J.L. Shisler, E.J. Roy Development of methodology: B. Tang, Z.S. Guo, G. McFadden, J.L. Shisler, E.J. Roy Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): B. Tang, D.Z. Yan, C.P. Schane, E.J. Roy |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-18-3626 |