CCR4 expression defines a targetable subset of T-cell acute lymphoblastic leukemia

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ABSTRACT: Patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis largely mediated by nonsustained responses to chemotherapy and few targeted therapy options. Surface antigen targets in T-ALL include CD2, CD5, CD7, and CD38; however, ongoing clinical development of these targets is challenged by (1) T-cell fratricide during manufacturing, (2) T-cell depletion during treatment, and (3) high frequency of target-negative relapse. Here, we use a combination of flow cytometry, single-cell genomics, and bulk RNA sequencing to identify CC chemokine receptor type 4 (CCR4) as a novel surface target in T-ALL. We analyzed the T-ALL microenvironment from 40 patients treated on the AALL0434 clinical trial and identified a subpopulation of bone marrow-enriched CCR4+ FOXP3+ T-regulatory cells that express immune checkpoints (PD-1 and TIGIT) and could be targeted with anti-CCR4 therapy. Finally, we describe the preclinical efficacy of an anti-CCR4 chimeric antigen receptor T-cell therapy in in vitro and in vivo models, paving the way for future translational efforts in chemotherapy-refractory T-ALL.

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