We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.
- Authors
Lee, Eric Hee Jun; Murad, John P.; Christian, Lea; Gibson, Jackson; Yamaguchi, Yukiko; Cullen, Cody; Gumber, Diana; Park, Anthony K.; Young, Cari; Monroy, Isabel; Yang, Jason; Stern, Lawrence A.; Adkins, Lauren N.; Dhapola, Gaurav; Gittins, Brenna; Chang, Wen-Chung; Martinez, Catalina; Woo, Yanghee; Cristea, Mihaela; Rodriguez-Rodriguez, Lorna
- 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. Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.
- Subjects
T cells; T cell receptors; TRANSMEMBRANE domains; CHIMERIC antigen receptors; TUMOR microenvironment; CELL physiology
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40115-1