American Association for Cancer Research
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Figure S1. from High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models

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posted on 2024-04-02, 07:23 authored by Émilie Degagné, Paul D. Donohoue, Suparna Roy, Jessica Scherer, Tristan W. Fowler, Ryan T. Davis, Gustavo A. Reyes, George Kwong, Morena Stanaway, Vanina Larroca Vicena, Devin Mutha, Raymond Guo, Leslie Edwards, Benjamin Schilling, McKay Shaw, Stephen C. Smith, Bryan Kohrs, Heinrich J. Kufeldt, Glen Churchward, Finey Ruan, David B. Nyer, Kyle McSweeney, Matthew J. Irby, Christopher K. Fuller, Lynda Banh, Mckenzi S. Toh, Matthew Thompson, Arthur L.G. Owen, Zili An, Scott Gradia, Justin Skoble, Mara Bryan, Elizabeth Garner, Steven B. Kanner

chRDNA-mediated gene editing did not result in any off-target editing above the limit of detection.

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Caribou Biosciences, Inc.

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ARTICLE 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 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.See related Spotlight by Caimi and Melenhorst, p. 385

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