Abstract
On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL7 receptor (IL7R), which promotes resistance to chemotherapy and disease relapse, here we develop IL7Rα (CD127)–targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments. We establish the antitumor efficacy of CD127 CAR against T-ALL cells in vitro, in female mouse models of T-ALL, and against blasts from patients with T-ALL using the patients’ own T cells transduced with CD127 CAR. Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells, albeit with fratricide of CAR T cells following eradication of CD127-overexpressing blasts. CRISPR-Cas9 knockout of CD127 eliminates fratricide at the risk of prolonged lymphopenia in vivo. To overcome fratricide, we investigate short-term ( < 7 days) co-culture with or without dasatinib, a tyrosine kinase inhibitor, versus a natural selection method (10 days) and demonstrate that co-culturing with dasatinib facilitates higher CAR T-cell yield, improved fitness, and preserved functionality. In vivo, dasatinib can be used to temporarily and reversibly suppress CAR T-cell activity. With this supporting translational data, we are initiating a trial with low-affinity CD127 CAR T cells for adult and pediatric patients with relapsed or refractory T-ALL.
Similar content being viewed by others
Acknowledgements
The scFvs used in the study were obtained from Drs. Nicholas Poirier and Aurore Morello of OSE Immunotherapeutics. Heather Alcorn and David B. Sewell of the Memorial Sloan Kettering Cancer Center Department of Surgery provided editorial assistance.
Funding
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (to Memorial Sloan Kettering Cancer Center), the Department of Pediatrics at MSK, RBC Race for Kids, and the Memorial Sloan Kettering Technology Development Fund. P.S.A.’s laboratory work is supported by grants from the National Institutes of Health (UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and T32CA009501), the U.S. Department of Defense (CA200437), the Adolfo F. Sardiña Charitable Foundation, the Batishwa Fellowship, the Baker Street Foundation, the Joanne and John DallePezze Foundation, the Derfner Foundation, the Esophageal Cancer Education Fund, the Memorial Sloan Kettering Technology Development Fund, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. P.S.A.’s laboratory receives research support from Novocure.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
P.S.A. declares research funding from Novocure; Scientific Advisory Board Member and/or Consultant for Affyimmune Therapeutics, Bio4t2, Carisma Therapeutics, Century Therapeutics, Orion Pharma, Outpace Bio, Pluri-biotech, and Verismo Therapeutics; patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center has previously licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and had associated financial interests. The remaining authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Hocine, H.R., Ganbaatar, U., Amador-Molina, A. et al. IL7-Receptor–Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia. Nat Commun (2026). https://doi.org/10.1038/s41467-026-75675-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-75675-5
- Springer Nature Limited