Qin and Dong et al. generated human CAR T cells specific for B cell activating factor receptor (BAFF-R), a lineage marker critical for B cell survival. BAFF-R-CAR T cells lysed human BAFF-R+ B cell tumors in vitro, releasing TNFα, IFNγ, and granzyme B. A single dose of BAFF-R-CAR T cells eliminated pre-established BAFF-R+CD19+and/or– B lymphoma xenografts, whereas CD19-CAR T cells allowed tumors to ultimately progress. BAFF-R- but not CD19- CAR T cells were activated in vitro by BAFF-R+CD19- primary escape variants obtained after CD19-targeted therapy, and reduced progression of a BAFF-R+ CD19- patient-derived xenograft.
Contributed by Paula Hochman
CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell-specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.
Author Info: (1) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (2) Toni St
Author Info: (1) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (2) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (3) Center for CAR T Cell Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (4) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (5) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan 910041, China. (6) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China. (7) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (8) Center for CAR T Cell Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (9) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (10) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (11) The Second Affiliated Hospital of Dalian Medical University, Dalian 116044, China. (12) Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, CA 90007, USA. (13) Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, CA 90007, USA. (14) Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (15) Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (16) Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA. (17) Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (18) Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. (19) Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. (20) Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (21) Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. (22) Center for CAR T Cell Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (23) Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. lkwak@coh.org.
