Patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis largely mediated by non-sustained 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 CCR4 as a novel surface target in T-ALL. We analyzed the T-ALL microenvironment from 40 T-ALL cases treated on the AALL0434 clinical trial and identified a subpopulation of bone-marrow-enriched CCR4+ FOXP3+ T-regulatory cells which express immune checkpoints (PD-1 and TIGIT) and could be targeted with anti-CCR4 therapy. Lastly, we describe the preclinical efficacy of an anti-CCR4 CAR-T in in vitro and in vivo models, paving the way for future translational efforts in chemotherapy refractory T-ALL.
Xu et al. (Wed,) studied this question.