Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma
Open Access
- 1 May 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (9), 2216-2230
- https://doi.org/10.1158/1078-0432.ccr-18-3626
Abstract
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 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. 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. 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.Keywords
Other Versions
Funding Information
- University of Illinois Institutional Funds
This publication has 66 references indexed in Scilit:
- IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent mannerProceedings of the National Academy of Sciences of the United States of America, 2013
- Myxoma Virus Sensitizes Cancer Cells to Gemcitabine and Is an Effective Oncolytic Virotherapeutic in Models of Disseminated Pancreatic CancerMolecular Therapy, 2012
- The Oncolytic Poxvirus JX-594 Selectively Replicates in and Destroys Cancer Cells Driven by Genetic Pathways Commonly Activated in CancersMolecular Therapy, 2012
- COX-2 Blockade Suppresses Gliomagenesis by Inhibiting Myeloid-Derived Suppressor CellsCancer Research, 2011
- Paradoxical Aspects of Rapamycin Immunobiology in TransplantationAmerican Journal of Transplantation, 2011
- Efficacy and Safety/Toxicity Study of Recombinant Vaccinia Virus JX-594 in Two Immunocompetent Animal Models of GliomaMolecular Therapy, 2010
- Optimized Peptide Vaccines Eliciting Extensive CD8 T-Cell Responses with Therapeutic Antitumor EffectsCancer Research, 2009
- Systemic Inhibition of Transforming Growth Factor-β in Glioma-Bearing Mice Improves the Therapeutic Efficacy of Glioma-Associated Antigen Peptide VaccinesClinical Cancer Research, 2009
- mTOR regulates memory CD8 T-cell differentiationNature, 2009
- Oncolytic Virotherapy Synergism with Signaling Inhibitors: Rapamycin Increases Myxoma Virus Tropism for Human Tumor CellsJournal of Virology, 2007