Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy

Kevin G. Shim, Shane Zaidi, Jill Thompson, Tim Kottke, Laura Evgin, Karishma R. Rajani, Matthew Schuelke, Christopher B. Driscoll, Amanda Huff, Jose S Pulido, Richard Geoffrey Vile

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy. We observed rapid expansion of blood CD8+ effector cells acutely following VSV therapy with markedly high expression of the immune checkpoint molecules PD-1 and TIM-3. Using these data, we tested a treatment schedule incorporating mAb immune checkpoint inhibitors with VSV+ACT treatment. Unlike clinical scenarios, we delivered therapy at early time points following tumor establishment and treatment. Our goal was to potentiate the immune response generated by VSV therapy to achieve durable control of metastatic disease. Despite the high frequency of endogenous PD-1+ TIM-3+ CD8+ T cells following virus administration, antibody blockade did not improve survival. These findings provide highly significant information about response kinetics to viroimmunotherapy and juxtapose the clinical use of checkpoint inhibitors against chronically dysfunctional T cells and the acute T cell response to oncolytic viruses.

Original languageEnglish (US)
Pages (from-to)962-975
Number of pages14
JournalMolecular Therapy
Volume25
Issue number4
DOIs
StatePublished - Apr 5 2017

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Keywords

  • checkpoint inhibitors
  • oncolytic virotherapy
  • tumor therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Shim, K. G., Zaidi, S., Thompson, J., Kottke, T., Evgin, L., Rajani, K. R., Schuelke, M., Driscoll, C. B., Huff, A., Pulido, J. S., & Vile, R. G. (2017). Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy. Molecular Therapy, 25(4), 962-975. https://doi.org/10.1016/j.ymthe.2017.01.023