A Rationally Designed Transgene Drives CAR T Functional Persistence and Durable Regression of Solid Tumors
Year: 2026
Type: preprint
Abstract: The eradication of solid tumors by chimeric antigen receptor (CAR) T cells requires dynamic therapies capable of outlasting an immune suppressive tumor microenvironment (TME). However, biological barriers—including rapid exhaustion, poor expansion, and loss of stem-like memory—quickly neutralize these therapies 1 . Because single-technology interventions often introduce unacceptable tradeoffs between efficacy and safety, durable remission demands a paradigm where multiple engineered solutions work in concert. To holistically address these mechanisms, we rationally designed a single-vector transgene that intrinsically drives CAR T functional persistence. The platform integrates four synergistic technologies: a high-avidity mesothelin (MSLN)-targeting CAR optimized to resist shed decoy antigens, a T-cell activation-responsive promoter (OUTLAST OP1) resisting exhaustion, a CD8α-targeted designed IL-2 cytokine (OUTSMART dIL-2) driving intratumoral CAR-T expansion, and an EGFRopt 2 safety switch. In lung and ovarian cancer models, this rational integration was required to drive antigen-dependent T cell expansion and eradicate established tumors at extremely low CAR T doses. Furthermore, engineered cells established a self-renewing pool of stem-like memory T cells capable of rejecting tumor rechallenge months later. Ultimately, this work demonstrates that intrinsic T cell dysfunction and extrinsic tumor-derived barriers can be simultaneously overcome by integrating synergistic technologies.
Authors: Rupesh H. Amin, Kevin G. Haworth, Howell F. Moffett, Jerry C. Chen, Lisa Park, Jason K. Yokoyama, Allan L. Wang, Leah J. Tait, Maria M. Steele, John T. Crowl, Thaddeus M. Davenport, Joseph DeSautelle, Jared L. Hammer, Willimark M. Obenza, Vanessa R. Montoya, Robin L. Kirkpatrick, Tina Tan, Kristie M. Shirley, Bradley Hammerson, Robert A. Langan, David S. Clausen, Paul J. Sample, Brian D. Weitzner, Shujun Yuan, Marc J. Lajoie, Scott E. Boyken, Aaron E. Foster
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7213978773