Focused on key challenges of CD19 CAR T cell therapy, such as on-target/off-tumor healthy B cell depletion and antigen-negative escape and relapse, Cohen, Bochi-Layec and Lemoine et al. developed CAR T cells targeting the BCR-carrying IGHV-34 (CART4-34), which is highly enriched in B cell cancers, SLE, and other autoimmune diseases. CART4-34 potently killed malignant B cells and pathogenic B cells in SLE ex vivo, while sparing normal IGHV-34-negative B cells. In preclinical models, CART4-34 showed robust expansion and antitumor activity, comparable to CART19, but was associated with reduced antigen-negative escape following treatment.
Contributed by Katherine Turner
ABSTRACT: Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34(+) serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34(+) malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34(+) BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34(+) HBL1 cell line-derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34(+) SLE B cells and deplete IGHV4-34(+) autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (12) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (13) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (14) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (15) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (16) Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (17) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. Division of Genetics and Biotechnology, Department of Biology, National and Kapodistrian University of Athens, Athens 15772, Greece. (20) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY 10065, USA. (23) LatchBio, San Francisco, CA 94107, USA. (24) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (26) Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (28) Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (30) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (31) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (32) Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (33) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (34) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (35) Institute of Hematology and Center for Hemato-Oncology Research, Department of Medicine and Surgery, University and Hospital of Perugia, Perugia 06129, Italy. (36) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (37) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (38) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (39) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (40) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (41) Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (42) Institute of Hematology and Center for Hemato-Oncology Research, Department of Medicine and Surgery, University and Hospital of Perugia, Perugia 06129, Italy. (43) Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (44) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (45) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (46) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (47) Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY 10065, USA. (48) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (49) Medical School, Universit Vita-Salute San Raffaele, Milan 20132, Italy. B cell Neoplasia Unit, Comprehensive Cancer Center, IRCCS Ospedale San Raffaele, Milan 20132, Italy. (50) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (51) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA.
