Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.

Abstract

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.

• Authors: Cesar Sommer, Bijan Boldajipour, Tracy C Kuo, Trevor Bentley, Janette Sutton, Amy Chen, Tao Geng, Holly Dong, Roman Galetto, Julien Valton, Thomas Pertel, Alexandre Juillerat, Annabelle Gariboldi, Edward Pascua, Colleen Brown, Sherman M Chin, Tao Sai, Yajin Ni, Philippe Duchateau, Julianne Smith, Arvind Rajpal, Thomas Van Blarcom, Javier Chaparro-Riggers, Barbra J Sasu
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 6 Pg. 1126-1138 (06 05 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 31005597 (Publication Type: Evaluation Study, Journal Article)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Immunological
• B-Cell Maturation Antigen
• Receptors, Chimeric Antigen
• Rituximab
• Transcription Activator-Like Effector Nucleases

Topics

• Animals
• Antineoplastic Agents, Immunological (therapeutic use)
• B-Cell Maturation Antigen (genetics, immunology)
• Blood Donors
• Cell Line, Tumor
• Cell Transplantation (adverse effects, methods)
• Cytotoxicity, Immunologic (genetics)
• Gene Editing
• Genetic Vectors
• Graft vs Host Disease (therapy)
• Humans
• Immunotherapy, Adoptive (adverse effects, methods)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Multiple Myeloma (pathology, therapy)
• Progression-Free Survival
• Receptors, Chimeric Antigen (genetics, immunology, metabolism)
• Rituximab (therapeutic use)
• T-Lymphocytes (immunology, metabolism, transplantation)
• Transcription Activator-Like Effector Nucleases (genetics)
• Transduction, Genetic
• Transplantation, Homologous (methods)