CD79b and CD19 are associated with B cell signaling and expressed on most B cell lymphomas. Ormhøj et al. show that CD79b expression persisted on a mantle cell lymphoma (MCL) line despite CD19 knockout in vitro. Chimeric antigen receptor (CAR) T cells specific for CD79b or CD19, or for CD79b plus CD19 were generated. All the CAR T cells lysed MCL cell lines in vitro and cleared CD79b+CD19+ MCLs in murine xenograft models. CD79b-specific CAR T cells and the bispecific CAR T cells also cleared CD79b+CD19- MCLs. Targeting CD79b with or without CD19 may provide benefit upfront or for CD19- lymphoma recurrence.
Contributed by Paula Hochman
PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma. CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.
Author Info: (1) Clinical Immunology, University of Southern Denmark. (2) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (3) Cancer Center, Massachusetts General Hospita
Author Info: (1) Clinical Immunology, University of Southern Denmark. (2) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (3) Cancer Center, Massachusetts General Hospital. (4) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (5) Duke University. (6) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (7) Cancer Center, Massachusetts General Hospital. (8) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (9) Cancer Center, Massachusetts General Hospital. (10) Cancer Center, Massachusetts General Hospital, Harvard Medical School. (11) Neurosurgery, Massachusetts General Hospital. (12) Cancer and Inflammation Research, University of Southern Denmark. (13) Haematology, Odense University Hospital. (14) Hematology, Aarhus University Hospital. (15) Haematology, Odense University Hospital. (16) Department of Cancer and Inflammation Research, University of Southern Denmark. (17) Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark. (18) Medical Oncology, Dana-Farber Cancer Institute. (19) Clinical Immunology, Odense University Hospital. (20) Bone Marrow Transplant/Cellular Therapy, Massachusetts General Hospital. (21) Cancer Center, Massachusetts General Hospital, Harvard Medical School mvmaus@mgh.harvard.edu.
