Evgin and Kottke et al. developed a regimen in which CAR T cells were preloaded in vitro with oncolytic viruses to enhance virus delivery to the LNs and stimulate the small fraction of CAR T cells with a native TCR reactive to viral or virus-encoded epitopes (dual-specific CARs) or epitope-specific endogenous T cells. TCR co-stimulation enhanced CAR T cell proliferation and antitumor functions in vivo, even without lymphodepletion, and induced a distinct memory phenotype. Antitumor efficacy was further enhanced by a homologous boost of virus. Treatment induced epitope spreading and resulted in durable cures in mice with subcutaneous melanoma and intracranial glioma.
Contributed by Lauren Hitchings
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.