Multiplex Genome-Edited T-cell Manufacturing Platform for 'Off-the-Shelf' Adoptive T-cell Immunotherapies
| Autor: | Gordon Weng-Kit Cheung, Agnès Gouble, Sophie Derniame, Roman Galetto, Justin Eyquem, Brian Philip, Cécile Schiffer-Mannioui, Pierrick Potrel, Julianne Smith, Karl S. Peggs, Aymeric Duclert, Cécile Bas, Andrew M. Scharenberg, Laetitia Lemaire, Martin Pule, Diane Le Clerre, Céline Lebuhotel, Sylvain Arnould, Laurent Poirot, Isabelle Chion-Sotinel |
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| Rok vydání: | 2014 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research CD52 Lymphoma medicine.medical_treatment T cell Receptors Antigen T-Cell alpha-beta Recombinant Fusion Proteins T-Lymphocytes Antigens CD19 Molecular Sequence Data Drug Resistance Receptors Antigen T-Cell Graft vs Host Disease Biology Antibodies Monoclonal Humanized Lymphocyte Activation Transfection Immunotherapy Adoptive Gene Knockout Techniques Mice Cancer immunotherapy Genome editing Antigen Antigens CD Antigens Neoplasm medicine Animals Humans RNA Messenger Alemtuzumab Glycoproteins Transcription activator-like effector nuclease Base Sequence Antibodies Monoclonal Immunotherapy Virology Xenograft Model Antitumor Assays Chimeric antigen receptor Mice Mutant Strains Cell biology medicine.anatomical_structure Oncology CD52 Antigen |
| Zdroj: | Cancer research. 75(18) |
| ISSN: | 1538-7445 |
| Popis: | Adoptive immunotherapy using autologous T cells endowed with chimeric antigen receptors (CAR) has emerged as a powerful means of treating cancer. However, a limitation of this approach is that autologous CAR T cells must be generated on a custom-made basis. Here we show that electroporation of transcription activator–like effector nuclease (TALEN) mRNA allows highly efficient multiplex gene editing in primary human T cells. We use this TALEN-mediated editing approach to develop a process for the large-scale manufacturing of T cells deficient in expression of both their αβ T-cell receptor (TCR) and CD52, a protein targeted by alemtuzumab, a chemotherapeutic agent. Functionally, T cells manufactured with this process do not mediate graft-versus-host reactions and are rendered resistant to destruction by alemtuzumab. These characteristics enable the administration of alemtuzumab concurrently or prior to engineered T cells, supporting their engraftment. Furthermore, endowing the TALEN-engineered cells with a CD19 CAR led to efficient destruction of CD19+ tumor targets even in the presence of the chemotherapeutic agent. These results demonstrate the applicability of TALEN-mediated genome editing to a scalable process, which enables the manufacturing of third-party CAR T-cell immunotherapies against arbitrary targets. As such, CAR T-cell immunotherapies can therefore be used in an “off-the-shelf” manner akin to other biologic immunopharmaceuticals. Cancer Res; 75(18); 3853–64. ©2015 AACR. |
| Databáze: | OpenAIRE |
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