CCR4 expression defines a targetable subset of T-cell acute lymphoblastic leukemia
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.
Authors
- Michael F. McCoy (ORCID: https://orcid.org/0000-0001-5215-2725)
- David T. Teachey (ORCID: https://orcid.org/0000-0001-7373-8987)
- Zachary Martinez
- Austin Yang
- Rawan Shraim (ORCID: https://orcid.org/0009-0005-5350-3386)
- Haley Newman (ORCID: https://orcid.org/0000-0002-3022-8052)
- Kai Tan
- Amanda M. DiNofia (ORCID: https://orcid.org/0000-0002-8321-0403)
- Hunter Wang (ORCID: https://orcid.org/0000-0003-3704-6611)
- Daniel Gao (ORCID: https://orcid.org/0000-0002-7825-6247)
- Caroline Diorio (ORCID: https://orcid.org/0000-0002-8005-3836)
- Stephan A. Grupp (ORCID: https://orcid.org/0000-0001-8030-7595)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Jiayi Xu (ORCID: https://orcid.org/0000-0003-3465-7927)
- SP Hunger
- Keanu Natan
- Connie Ma
- Omar Elghawy
- Jun J Yang
- Ted J Hofmann
- Charles G. Mullighan
- Petri Pölönen
- Carl H. June
- Elizabeth O Hexner
- Keisuke Watanabe
- Gregory M Chen
- Samantha Scoma
- Tiffaney L Vincent
- Jonathan H. Sussman
Institutions
- St. Jude Children's Research Hospital (US)
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2026-02-11
- DOI
- https://doi.org/10.1182/bloodadvances.2025018600
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Amgen
- AstraZeneca
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Servier
- Swedish Orphan Biovitrum
- National Institutes of Health
- National Cancer Institute