Peptide-MHC–targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells

作者：Ellen J. K. Xu, Blake E. Smith, Winiffer D. Conce Alberto, Michael J. Walsh, Birkley Lim, Megan T. Hoffman, Qiang Li, Ariana E. Barreiro, Emma N Finburgh, Jiayi Dong, Andrea Garmilla, Qingyang Henry Zhao, Caleb R. Perez, Stephanie Gaglione, Connor S. Dobson, Michael Dougan, Stephanie K. Dougan, Michael E. Birnbaum · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adv2331 · 被引用次数：2 · 研究领域：Virus-based gene therapy research、CAR-T cell therapy research、Immunotherapy and Immune Responses

Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate effective antitumor responses. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions that can affect treatment efficacy. Therefore, additional tools are needed to engineer TILs to have increased potency while mitigating manufacturing challenges. Here, we present a strategy for pseudotyping retroviruses with peptide-major histocompatibility complexes (pMHCs) for antigen-specific gene delivery to CD8 T cells and validate therapeutic impact in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses specifically deliver function-enhancing cargos while simultaneously activating and expanding antitumor T cells. This targeting precision enables in vivo engineering of tumor-specific T cells, resulting in improved overall survival in B16F10-bearing mice. Together, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific T cells directly in vivo, with the potential to substantially streamline engineered cell therapy production.