| Autor: |
Eric Hee Jun Lee, John P. Murad, Lea Christian, Jackson Gibson, Yukiko Yamaguchi, Cody Cullen, Diana Gumber, Anthony K. Park, Cari Young, Isabel Monroy, Jason Yang, Lawrence A. Stern, Lauren N. Adkins, Gaurav Dhapola, Brenna Gittins, Wen-Chung Chang, Catalina Martinez, Yanghee Woo, Mihaela Cristea, Lorna Rodriguez-Rodriguez, Jun Ishihara, John K. Lee, Stephen J. Forman, Leo D. Wang, Saul J. Priceman |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-16 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-40115-1 |
| Popis: |
Abstract Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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