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

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.

Current landscape and perspective of oncolytic viruses and their combination therapies

“…On the other hand, OVs penetrates into the tumor cells to replicate and lyse tumor cells and trigger an immune response that facilitates CAR-T cell attacks on surviving tumor cells. Intravenous administration of OV-loaded CAR-T cells showed good efficacy in mouse melanoma and glioma tumor models, with improved survival [98] . This study provides an innovative approach to the treatment of solid tumors with OVs in combination with CAR-T cells.…”

Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancements

“…Although there are strong scientific rationales and preclinical evidence that support the combination of OV with CAR-T cells to induce synergistic antitumor efficacy, there are growing evidence that contrarily demonstrate that OV-induced type I IFN response can be detrimental to the functionality of T cells, including CAR-T cells, and induce their apoptotic cell death ( 48 , 247 , 248 ). One promising strategy to circumvent this issue is to infect the CAR-T cells directly with OVs which enables systemic delivery of both CAR-T cell and OV to solid tumors ( 249 ). In detail, dual-specific CAR-T cells that recognizes viral antigens of the OVs and EGFR of tumors infected with oncolytic reovirus or vesicular stomatitis virus (VSV) exhibited augmented proliferation and biological function due to stimulation of native T cell receptor by viral epitopes.…”

Prospective approaches to enhancing CAR T cell therapy for glioblastoma

“…Infected tumor cells with an oncolytic vaccinia virus coding for CD19t (OV19t) produces de novo CD19 at the cell surface and subsequent virus-mediated tumor cytolysis ( 68 ). Recently, another OV study revealed that induction of the native TCR with viral or virally encoded epitopes enhances CAR T cell proliferation, activity, and efficacy in mice with intracranial GBM tumors ( 69 ).…”