Nature communicationsJul 15, 2026

CAR T-Cell Therapy Targeting IL7 Receptor for T-Cell Acute Lymphoblastic Leukemia

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Updated Jul 16, 2026

Abstract

Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells against T-cell acute lymphoblastic leukemia (T-ALL).

IL7 receptor (IL7R) is overexpressed in T-ALL cells, which may lead to chemotherapy resistance and disease relapse.
CD127-targeted CAR T cells demonstrate effectiveness against T-ALL in laboratory settings and in female mouse models.
Fratricide occurs among CAR T cells after eliminating CD127-overexpressing blasts, impacting treatment outcomes.
CRISPR-Cas9 technology can knockout CD127 to reduce fratricide but may lead to prolonged low lymphocyte levels in the body.
Co-culturing CAR T cells with dasatinib enhances their yield and functionality while allowing for temporary suppression of activity.

Simplified

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.

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Funding

Competing interests

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.

PubMed

CAR T-Cell Therapy Targeting IL7 Receptor for T-Cell Acute Lymphoblastic Leukemia

Abstract

Full Text

Funding

Competing interests

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