Effective Targeting of Multiple B-Cell Maturation Antigen–Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells

Abstract

B-cell maturation antigen (BCMA) expression has been proposed as a marker for the identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Consistent BCMA expression was confirmed on MM biopsies (29/29 BCMA+), and it was further demonstrated that BCMA is expressed in a substantial number of lymphoma samples, as well as primary chronic lymphocytic leukemia B cells. To target BCMA using redirected autologous T cells, lentiviral vectors (LVV) encoding chimeric antigen receptors (CARs) were constructed with four unique anti-BCMA single-chain variable fragments, fused to the CD137 (4-1BB) co-stimulatory and CD3ζ signaling domains. One LVV, BB2121, was studied in detail, and BB2121 CAR-transduced T cells (bb2121) exhibited a high frequency of CAR + T cells and robust in vitro activity against MM cell lines, lymphoma cell lines, and primary chronic lymphocytic leukemia peripheral blood. Based on receptor quantification, bb2121 recognized tumor cells expressing as little as 222 BCMA molecules per cell. The in vivo pharmacology of anti-BCMA CAR T cells was studied in NSG mouse models of human MM, Burkitt lymphoma, and mantle cell lymphoma, where mice received a single intravenous administration of vehicle, control vector-transduced T cells, or anti-BCMA CAR-transduced T cells. In all models, the vehicle and control CAR T cells failed to inhibit tumor growth. In contrast, treatment with bb2121 resulted in rapid and sustained elimination of the tumors and 100% survival in all treatment models. Together, these data support the further development of anti-BCMA CAR T cells as a potential treatment for not only MM but also some lymphomas.

Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

“…Next, we reversed this approach and used a BCMA-specific DARIC with a CD19 plug-in. The BCMA-DARIC construct is similar in design to the CD19-DARIC but utilizes a BCMA-specific scFv (35). We took cultures of BCMA-DARIC in the "off position" without the addition of rapamycin and added the CD19 plug-in that had been prebound with rapamycin and cultured these cells with BCMA -CD19 + Nalm-6 cells.…”

Molecular design, optimization and genomic integration of chimeric B cell receptors in murine B cells

“…50 , maintained in high-glucose DMEM containing GlutaMAX supplemented with 10% FBS and 100 U ml -1 and passaged at 90% confluence. To prepare the feeder layer, 40LB cells were plated at 4 x 10 4 per cm 2 about 16 h before co-culture and irradiated with 60 Gy γ–ray. Splenic B cells were pre-activated in a T-75 flask in the presence of irradiated 40LB feeder cells in 40 ml RPMI-1630 medium supplemented with 10% FBS (consistently coming from the same batch), 1 mM Na-Pyruvate, 10 mM HEPES buffer, 100 U ml -1 Penicillin/Streptomycin and 50 μM 2-Mercapotethanol for 24 h. rIL-4 (1 ng ml -1 , Peprotech) was added to the primary culture for four days.…”

“…The successful clinical results of genetically modified T cells for cancer immunotherapy have shown the great potential for engineering immune cells for cellular medicine 1,2,3,4 . Engineered CD8 + T cells have shown the most progress as they can execute cytotoxic functions by inducing target cells to undergo programmed cell death 5 , thus providing a means to directly attack cancer cells.…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…They are both second-generation CARs targeting the B-cell lineage antigen CD19 [14,15,17]. Regulatory approval for other second-generation CARs targeting different B-cell markers, most notably B-cell maturation antigen (BCMA) [18,19], are anticipated in the coming years.…”