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.
Author Info: (1) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (2) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (3) Department of Molecula
Author Info: (1) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (2) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (3) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (4) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (5) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (6) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (7) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (8) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (9) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (10) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (11) Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA. (12) Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA. (13) Oncolytics Biotech Incorporated, Calgary, AB, Canada. (14) Oncolytics Biotech Incorporated, Calgary, AB, Canada. (15) Department of Neurosurgery, Duke University, Durham, NC 27710, USA. (16) Mayo Clinic Ventures, Mayo Clinic, Rochester, MN 55905, USA. (17) Division of Radiotherapy and Imaging, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK. (18) Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK. (19) Division of Radiotherapy and Imaging, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK. (20) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (21) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
