Data from High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models

Arthur L.G Owen,Benjamin Schilling,Bryan Kohrs,Christopher K Fuller,David B Nyer,Devin Mutha,Elizabeth Garner,ÉMilie Degagné,Finey Ruan,George Kwong,Glen Churchward,Gustavo A Reyes,Heinrich J Kufeldt,Jessica Scherer,Justin Skoble,Kyle Mcsweeney,Leslie Edwards,Lynda Banh,Mara Bryan,Matthew J Irby,Matthew Thompson,Mckay Shaw,Mckenzi S Toh,Morena Stanaway,Paul D Donohoue,Raymond Guo,Ryan T Davis,Scott Gradia,Stephen C Smith,Steven B Kanner,Suparna Roy,Tristan W Fowler,Vanina Larroca Vicena,Zili An

doi:10.1158/2326-6066.c.7160258

Abstract

<div>AbstractAllogeneic 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 graft-vs-host disease (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 HLA class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. In addition, 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 cocultures derived from patients with multiple myeloma. In addition, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer 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.<a href="https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-24-0204" target="_blank">See related Spotlight by Caimi and Melenhorst, p. 385</a></div>

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