Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice

Laura Evgin, Tim Kottke, Jason Tonne, Jill Thompson, Amanda L. Huff, Jacob van Vloten, Madelyn Moore, Josefine Michael, Christopher Driscoll, Jose S Pulido, Eric Swanson, Richard Kennedy, Matt Coffey, Houra Loghmani, Luis Sanchez-Perez, Gloria Olivier, Kevin Harrington, Hardev Pandha, Alan Melcher, Rosa Maria DiazRichard G. Vile

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)eabn2231
JournalScience translational medicine
Volume14
Issue number640
DOIs
StatePublished - Apr 13 2022

ASJC Scopus subject areas

  • Medicine(all)

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