Diverse immunotherapies can effectively treat syngeneic brainstem tumors in the absence of overt toxicity

Matthew R. Schuelke, Phonphimon Wongthida, Jill Thompson, Timothy Kottke, Christopher B. Driscoll, Amanda L. Huff, Kevin G. Shim, Matt Coffey, Jose S Pulido, Laura Evgin, Richard Geoffrey Vile

Research output: Contribution to journalArticle

Abstract

Background: Immunotherapy has shown remarkable clinical promise in the treatment of various types of cancers. However, clinical benefits derive from a highly inflammatory mechanism of action. This presents unique challenges for use in pediatric brainstem tumors including diffuse intrinsic pontine glioma (DIPG), since treatment-related inflammation could cause catastrophic toxicity. Therefore, the goal of this study was to investigate whether inflammatory, immune-based therapies are likely to be too dangerous to pursue for the treatment of pediatric brainstem tumors. Methods: To complement previous immunotherapy studies using patient-derived xenografts in immunodeficient mice, we developed fully immunocompetent models of immunotherapy using transplantable, syngeneic tumors. These four models-HSVtk/GCV suicide gene immunotherapy, oncolytic viroimmunotherapy, adoptive T cell transfer, and CAR T cell therapy-have been optimized to treat tumors outside of the CNS and induce a broad spectrum of inflammatory profiles, maximizing the chances of observing brainstem toxicity. Results: All four models achieved anti-tumor efficacy in the absence of toxicity, with the exception of recombinant vaccinia virus expressing GMCSF, which demonstrated inflammatory toxicity. Histology, imaging, and flow cytometry confirmed the presence of brainstem inflammation in all models. Where used, the addition of immune checkpoint blockade did not introduce toxicity. Conclusions: It remains imperative to regard the brainstem with caution for immunotherapeutic intervention. Nonetheless, we show that further careful development of immunotherapies for pediatric brainstem tumors is warranted to harness the potential potency of anti-tumor immune responses, despite their possible toxicity within this anatomically sensitive location.

Original languageEnglish (US)
Article number188
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Jul 17 2019

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Keywords

  • Brainstem
  • DIPG
  • Immunotherapy
  • Toxicity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Schuelke, M. R., Wongthida, P., Thompson, J., Kottke, T., Driscoll, C. B., Huff, A. L., Shim, K. G., Coffey, M., Pulido, J. S., Evgin, L., & Vile, R. G. (2019). Diverse immunotherapies can effectively treat syngeneic brainstem tumors in the absence of overt toxicity. Journal for ImmunoTherapy of Cancer, 7(1), [188]. https://doi.org/10.1186/s40425-019-0673-2