IL7-Receptor Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia
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
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.
This study demonstrates that low‑affinity CD127‑targeted CAR T cells are more effective than high‑affinity CAR T cells in controlling T‑ALL in vitro and in vivo, but highlights the challenge of fratricide and the potential role of dasatinib to mitigate it during manufacturing. The findings provide a rationale for a clinical trial of low‑affinity CD127 CAR T cells in relapsed or refractory T‑ALL patients.
Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.
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