CAR T-cell Efficacy in Solid Tumors Is Enhanced by Oncolytic Viruses

Oncolytic viruses (OV) that encode a variety of transgenes have been used to improve the efficacy of chimeric antigen receptor (CAR) T-cell therapy in solid tumors. Previous work, however, has shown both useful and negative consequences of OVs in CAR therapy, so Evgin, Kottke, and colleagues sought alternative strategies to improve upon this coadministration in immunocompetent mouse models. As previous studies indicated that preconditioning of the tumor with oncolytic vesicular stomatitis virus (VSV) expressing mouse interferon-β (VSV-mIFNβ) led to CAR T-cell attrition, a new schedule of administration of CAR T cells followed by intratumoral or intravenous injection of VSV-mIFNβ 5 days later was used and showed selective expansion of CD8 CARs exhibiting native T-cell receptor (TCR) specificity to the VSV immunodominant epitope, VSV N_52-59, with this expansion being greater after intravenous injection. Moreover, these double-specific (DS) CARs expanded to approximately 10% to 20% of the CD8 CAR T-cell population in vivo, suggesting a selective advantage for their expansion and survival. Further investigation revealed their capacity for degranulation and cytokine production, and loading of these CARs with VSV improved viral delivery to both tumors and lymph nodes, with these CARs demonstrating greater functionality and IFNγ secretion. Additionally, these DS CARs conferred a survival advantage in a murine melanoma tumor model. This phenotype was not dependent on virus or tumor type, as similar results were observed with reovirus and intracranial tumors. Furthermore, CAR T cells generated from mice that were previously immunized with reovirus and were further virally preloaded demonstrated enhanced survival, suggesting that reactivating virus-specific memory CAR T cells boosts immune activity. CAR T cells targeting viral or virally encoded antigens, like human gp100, also demonstrated enhanced therapeutic efficacy and effectiveness against lowly expressed antigens. These phenotypes were also observed with human CAR T cells in vitro, supporting the use of virus-loaded CARs in solid tumors. In summary, this study shows viral loading of CAR T cells or activation of the native TCR improves therapy response with a systemic boost of OV leading to long-term disease cures, suggesting this approach could improve CAR efficacy in solid tumors.

Evgin L, Kottke T, Tonne J, Thompson J, Huff AL, van Vloten J, et al. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Sci Transl Med 2022;14:eabn2231.

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