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