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Oncolytic virus-derived type I interferon restricts CAR T cell therapy

Laura Evgin1, Amanda L Huff1, Phonphimon Wongthida1

  • 1Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.

Nature Communications
|June 26, 2020
PubMed

Insights

Oncolytic viruses, when combined with chimeric antigen receptor (CAR) T cells for solid tumors, unexpectedly caused CAR T cell loss. Interferon-insensitive CAR T cells are needed for effective combination therapy.

Area of Science:

  • Immunology
  • Oncology
  • Virology

Background:

  • Adoptive T cell therapies, including chimeric antigen receptor (CAR) T cells, are promising for solid tumors but face challenges from the tumor microenvironment.
  • Combinatorial strategies are crucial to enhance CAR T cell efficacy against solid tumors.

Purpose of the Study:

  • To investigate if oncolytic viruses can enhance CAR T cell therapy for solid tumors by modulating the tumor microenvironment.
  • To understand the interaction between oncolytic viruses and CAR T cells in a preclinical solid tumor model.

Main Methods:

  • Utilized a murine B16EGFRvIII solid tumor model.
  • Administered VSVmIFNβ oncolytic virus and EGFRvIII CAR T cells.
  • Analyzed CAR T cell survival, function, and tumor microenvironment changes, including chemokine profiles and type I interferon induction.

Main Results:

  • VSVmIFNβ infection led to attrition of murine EGFRvIII CAR T cells, contrary to the hypothesis.
  • Oncolytic virus infection induced a proinflammatory chemokine profile but also promoted CAR T cell apoptosis and exhaustion via type I interferon.
  • CAR T cells engineered to be insensitive to interferon demonstrated improved efficacy in combination therapy.

Conclusions:

  • Oncolytic viruses can interfere with CAR T cell therapy through type I interferon-mediated mechanisms.
  • Developing interferon-insensitive CAR T cells is essential for successful combination strategies with oncolytic viruses.
  • Further research is needed to optimize the combination of CAR T cells and oncolytic viruses for solid tumor treatment.

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