A Rationally Designed Transgene Drives CAR T Functional Persistence and Durable Regression of Solid Tumors
- 1Outpace Bio
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. 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 CD8-targeted designed IL-2 cytokine (OUTSMART dIL-2) driving intratumoral CAR-T expansion, and an EGFRopt 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.
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BibTeX
@misc{amin2026rationally,
title = {{A Rationally Designed Transgene Drives CAR T Functional Persistence and Durable Regression of Solid Tumors}},
author = {R. H. Amin and K. G. Haworth and H. F. Moffett and J. C. Chen and L. Park and J. K. Yokoyama and A. L. Wang and L. J. Tait and M. M. Steele and J. T. Crowl and T. M. Davenport and J. DeSautelle and J. L. Hammer and W. M. Obenza and V. R. Montoya and R. L. Kirkpatrick and T. Tan and K. M. Shirley and B. Hammerson and R. A. Langan and D. S. Clausen and P. J. Sample and B. D. Weitzner and S. Yuan and M. J. Lajoie and S. E. Boyken and A. E. Foster},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752754},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752754v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Rationally Designed Transgene Drives CAR T Functional Persistence and Durable Regression of Solid Tumors
AU - R. H. Amin
AU - K. G. Haworth
AU - H. F. Moffett
AU - J. C. Chen
AU - L. Park
AU - J. K. Yokoyama
AU - A. L. Wang
AU - L. J. Tait
AU - M. M. Steele
AU - J. T. Crowl
AU - T. M. Davenport
AU - J. DeSautelle
AU - J. L. Hammer
AU - W. M. Obenza
AU - V. R. Montoya
AU - R. L. Kirkpatrick
AU - T. Tan
AU - K. M. Shirley
AU - B. Hammerson
AU - R. A. Langan
AU - D. S. Clausen
AU - P. J. Sample
AU - B. D. Weitzner
AU - S. Yuan
AU - M. J. Lajoie
AU - S. E. Boyken
AU - A. E. Foster
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752754
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752754v1
AB - 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. 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 CD8-targeted designed IL-2 cytokine (OUTSMART dIL-2) driving intratumoral CAR-T expansion, and an EGFRopt 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.
ER -