TY - JOUR
T1 - Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma
AU - Tang, Bingtao
AU - Guo, Zong Sheng
AU - Bartlett, David L.
AU - Yan, David Z.
AU - Schane, Claire P.
AU - Thomas, Diana L.
AU - Liu, Jia
AU - McFadden, Grant
AU - Shisler, Joanna L.
AU - Roy, Edward J.
AU - Roy, Edward J.
N1 - Funding Information:
This research was funded by institutional funds from the University of Illinois Urbana-Champaign. We thank the people of the Biotechnology Center Flow Cytometry facility for cheerful and competent service. B. Tang is supported by the Carle Foundation Hospital and University of Illinois Cancer Scholars for Translational and Applied Research (C*STAR) Graduate Program. We thank Dr. David Kranz for generously sharing his laboratory facilities and expertise for the last 26 years.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Purpose: We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an antiimmunosuppressant 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. Experimental Design: 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. Results: 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 prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDDIL15Rα- 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. Conclusions: IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib.
AB - Purpose: We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an antiimmunosuppressant 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. Experimental Design: 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. Results: 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 prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDDIL15Rα- 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. Conclusions: 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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U2 - 10.1158/1078-0432.CCR-18-3626
DO - 10.1158/1078-0432.CCR-18-3626
M3 - Article
C2 - 32019860
AN - SCOPUS:85084961147
VL - 26
SP - 2216
EP - 2230
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 9
ER -