Peptide-MHC–targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells
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.
Authors
- Michael E. Birnbaum (ORCID: https://orcid.org/0000-0002-2281-3518)
- Stephanie K. Dougan (ORCID: https://orcid.org/0000-0002-2263-363X)
- Ellen Janine Kim (ORCID: https://orcid.org/0000-0003-4766-9919)
- Winiffer D. Conce Alberto (ORCID: https://orcid.org/0000-0002-4097-9861)
- Caleb R. Perez (ORCID: https://orcid.org/0000-0001-8709-6145)
- Megan T. Hoffman (ORCID: https://orcid.org/0000-0003-0907-9977)
- Jiayi Dong (ORCID: https://orcid.org/0000-0003-4028-1057)
- Michael J. Walsh (ORCID: https://orcid.org/0000-0002-1283-6847)
- Connor S. Dobson (ORCID: https://orcid.org/0000-0001-6486-536X)
- Michael Dougan (ORCID: https://orcid.org/0000-0001-9266-2009)
- Emma N Finburgh (ORCID: https://orcid.org/0009-0005-6287-754X)
- Stephanie Gaglione (ORCID: https://orcid.org/0000-0002-4067-0178)
- Ariana E. Barreiro
- Andrea Garmilla (ORCID: https://orcid.org/0000-0002-5093-1423)
- Blake E. Smith (ORCID: https://orcid.org/0000-0001-9878-8198)
- Qingyang Henry Zhao (ORCID: https://orcid.org/0000-0002-6757-7504)
- Qiang Li (ORCID: https://orcid.org/0000-0002-2354-177X)
- Birkley Lim (ORCID: https://orcid.org/0009-0005-7558-9168)
Institutions
- Harvard University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Allen Institute (US)
- Singapore-MIT Alliance for Research and Technology (SG)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1126/sciadv.adv2331
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00