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Updated: Sep 27, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice
Laura Evgin1, Tim Kottke1, Jason Tonne1
1Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-modified T cells in the solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR T cells in immunocompetent mouse models, we have defined a mechanism by which OVs can potentiate CAR T cell efficacy against solid tumor models of melanoma and glioma. We show that stimulation of the native T cell receptor (TCR) with viral or virally encoded epitopes gives rise to enhanced proliferation, CAR-directed antitumor function, and distinct memory phenotypes. In vivo expansion of dual-specific (DS) CAR T cells was leveraged by in vitro preloading with oncolytic vesicular stomatitis virus (VSV) or reovirus, allowing for a further in vivo expansion and reactivation of T cells by homologous boosting. This treatment led to prolonged survival of mice with subcutaneous melanoma and intracranial glioma tumors. Human CD19 CAR T cells could also be expanded in vitro with TCR reactivity against viral or virally encoded antigens and was associated with greater CAR-directed cytokine production. Our data highlight the utility of combining OV and CAR T cell therapy and show that stimulation of the native TCR can be exploited to enhance CAR T cell activity and efficacy in mice.
Insights
Oncolytic viruses (OVs) enhance chimeric antigen receptor (CAR) T cell therapy by stimulating the T cell receptor (TCR) with viral epitopes. This combination improves anti-tumor function and survival in solid tumor models.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Oncolytic viruses (OVs) are explored to boost chimeric antigen receptor (CAR) T cell efficacy in solid tumors.
- The tumor microenvironment (TME) presents challenges for CAR T cell function.
Purpose of the Study:
- To define the mechanism by which OVs enhance CAR T cell efficacy in solid tumors.
- To evaluate the combination of systemically delivered OVs and CAR T cells in immunocompetent mouse models.
Main Methods:
- Systemic delivery of OVs and CAR T cells in mouse models of melanoma and glioma.
- In vitro preloading of CAR T cells with oncolytic vesicular stomatitis virus (VSV) or reovirus.
- Assessment of T cell proliferation, anti-tumor function, and memory phenotypes.
Main Results:
- Viral or virally encoded epitopes stimulate the native T cell receptor (TCR), enhancing CAR T cell proliferation and anti-tumor function.
- In vitro preloading and homologous boosting led to in vivo expansion and reactivation of dual-specific (DS) CAR T cells.
- Combination therapy significantly prolonged survival in melanoma and glioma models.
Conclusions:
- Stimulating the native TCR with viral epitopes is a viable strategy to enhance CAR T cell activity and efficacy.
- Combining OV and CAR T cell therapy offers a promising approach for treating solid tumors.
- This strategy improves CAR T cell function and survival outcomes in preclinical models.
