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...

Full description

Saved in:
Bibliographic Details
Published inClinical cancer research Vol. 26; no. 9; pp. 2216 - 2230
Main Authors Tang, Bingtao, Guo, Zong Sheng, Bartlett, David L, Yan, David Z, Schane, Claire P, Thomas, Diana L, Liu, Jia, McFadden, Grant, Shisler, Joanna L, Roy, Edward J
Format Journal Article
LanguageEnglish
Published United States 01.05.2020
Subjects
Online AccessGet full text

Cover

Loading…
More Information
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.
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