Hanina et al. demonstrated that CD70 is heterogeneously expressed in solid tumors ranging to ultra-low, due to epigenetic silencing of CD70 by EZH2-mediated H3K27 trimethylation. Conventional detection assays were unable to detect ultra-low levels of CD70, and commonly used CARs failed to achieve complete tumor clearance. A more sensitive CD70-targeted CAR T cell utilizing a VH/VL-engineered HLA-independent T cell receptor (HIT) eradicated heterogeneous tumors, without additional toxicity, in xenograft models of multiple cancers. An epigenetic signature based on CD70 chromatin accessibility detected ultra-low expression and HIT sensitivity.
Contributed by Shishir Pant
ABSTRACT: Solid tumor antigen heterogeneity is a major challenge for cancer immunotherapies, including chimeric antigen receptor (CAR) T cells. Unlike CD19 for B cell malignancies, no target with pan-cellular expression in solid tumors and absence in normal vital cells has been identified. CD70 is a promising candidate, physiologically confined to immune cell subsets and aberrantly expressed in many cancers. We show that heterogeneous CD70 expression in tumors is epigenetically regulated, ranging from high to very low in individual cells, appearing negative by conventional detection methods. Using a highly sensitive CD70 receptor, HLA-independent T cell (HIT) receptor coexpressing CD80 and 4-1BBL for costimulation, we efficiently eliminated CD70-heterogeneous tumors that evade prototypic CAR T cells. These findings provide a potential strategy to treat a broad range of solid tumors.
Author Info: (1) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA. (2) Compu
Author Info: (1) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA. (2) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA. (4) Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA. (7) Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA. (10) Bio-Imaging Resource Center, The Rockefeller University, New York, NY USA. (11) Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA. (15) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Columbia Initiative in Cell Engineering and Therapy (CICET), Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY USA.
