Allogeneic CB-011 CAR T cells were engineered with (1) an anti-BCMA CAR at the TRAC locus, to disrupt endogenous TCR expression and prevent GvHD, and (2) a B2M-HLA-E complex at the B2M locus, to avoid HLA-mismatch allograft rejection and NK cell killing. CB-011 lysed BCMA+ cell lines and patient-derived multiple myeloma (MM) cells in vitro, and treated a MM mouse model without signs of GvHD. Compared to CAR T cells without HLA knockout or B2M-HLA-E insertion, CB-011 resisted HLA-mismatched T cell lysis or NK cell killing, respectively. In NK cell-engrafted mice, CB-011 cells persisted and had lower genomic stress signatures than CAR T cells with B2M KO alone.
Contributed by Alex Najibi
ABSTRACT: Allogeneic chimeric antigen receptor (CAR) T-cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T-cell therapies include prevention of GvHD and suppression of allograft rejection. Here we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B cell maturation antigen (BCMA) CAR T-cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR T cells were engineered to prevent endogenous human leukocyte antigen (HLA) class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. Additionally, T-cell receptor (TCR) expression was disrupted at the TCR alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell co-cultures derived from patients with multiple myeloma. Additionally, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer (NK) cell-mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M-HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma.
Author Info: (1) Caribou Biosciences (United States), Berkeley, CA, United States. (2) Caribou Biosceinces, Inc., Berkeley, CA, United States. (3) Caribou Biosciences (United States), Berkeley,
Author Info: (1) Caribou Biosciences (United States), Berkeley, CA, United States. (2) Caribou Biosceinces, Inc., Berkeley, CA, United States. (3) Caribou Biosciences (United States), Berkeley, CA, United States. (4) Caribou Biosciences (United States), Berkeley, CA, United States. (5) Caribou Biosceinces, Inc., Berkeley, CA, United States. (6) Caribou Biosciences (United States), Berkeley, CA, United States. (7) Caribou Biosciences (United States), Berkeley, CA, United States. (8) Caribou Biosciences, Inc., Berkeley, CA, United States. (9) Caribou Biosciences (United States), Berkeley, CA, United States. (10) Caribou Biosciences (United States), Berkeley, CA, United States. (11) Caribou Biosciences (United States), Berkeley, CA, United States. (12) Caribou Biosciences (United States), Berkeley, CA, United States. (13) Caribou Biosceinces, Inc., Berkeley, CA, United States. (14) Caribou Biosciences (United States), Berkeley, CA, United States. (15) Caribou Biosciences (United States), Berkeley, CA, United States. (16) Caribou Biosciences (United States), Berkeley, CA, United States. (17) Caribou Biosceinces, Inc., Berkeley, CA, United States. (18) caribou biosciences, United States. (19) caribou biosciences, United States. (20) caribou biosciences, United States. (21) caribou biosciences, United States. (22) Adicet Bio, Redwood City, CA, United States. (23) Caribou Biosceinces, Inc., Berkeley, CA, United States. (24) Caribou Biosciences (United States), Berkeley, CA, United States. (25) Caribou Biosciences (United States), Berkeley, CA, United States. (26) Caribou Biosciences (United States), Berkeley, CA, United States. (27) Caribou Biosciences (United States), Berkeley, CA, United States. (28) Caribou Biosciences (United States), Berkeley, CA, United States. (29) Caribou Biosciences (United States), Berkeley, CA, United States. (30) Caribou Biosciences (United States), Berkeley, CA, United States. (31) Caribou Biosciences (United States), Berkeley, CA, United States. (32) Caribou Biosciences (United States), Berkeley, CA, United States. (33) Caribou Biosciences (United States), Berkeley, CA, United States. (34) Caribou Biosceinces, Inc., Berkeley, CA, United States.
