Engagement of the TCR against an oncolytic virus generates a population of effector CAR T cells with potent antitumor activity

作者：Olivia Liseth, Elizabeth Appleton, Benjamin Kendall, Jill Thompson, Thanich Sangsuwannukul, Jason Tonne, Rosa María Díaz, Laura Evgin, Anton Patrikeev, Nicolás Sarbia, Shane Foo, K. Harrington, Masahiro Ono, Alan Melcher, Richard Vile · 发表于：Science Advances · 年份：2026 · DOI：10.1126/sciadv.aef5331 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Viral Infectious Diseases and Gene Expression in Insects

Chimeric antigen receptor (CAR) T cell therapy faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous T cell receptor (TCR) using an oncolytic virus enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to non-TCR-primed CAR T cells. Single-cell RNA sequencing showed clonal expansion of anti-VSV CAR T cells and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in the development of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of systemic oncolytic virotherapy and for directly exploiting the CAR T cell TCR to fine tune the CAR T cell phenotype and function.