1. Multiplex Genome-Edited T-cell Manufacturing Platform for "Off-the-Shelf" Adoptive T-cell Immunotherapies.
- Author
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Poirot, Laurent, Philip, Brian, Schiffer-Mannioui, Cécile, Le Clerre, Diane, Chion-Sotinel, Isabelle, Derniame, Sophie, Potrel, Pierrick, Bas, Cécile, Lemaire, Laetitia, Galetto, Roman, Lebuhotel, Céline, Eyquem, Justin, Cheung, Gordon Weng-Kit, Duclert, Aymeric, Gouble, Agnès, Arnould, Sylvain, Peggs, Karl, Pule, Martin, Scharenberg, Andrew M., and Smith, Julianne
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T cells , *CANCER genetics , *IMMUNOTHERAPY , *ANTIGEN receptors , *CANCER research - Abstract
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 aCD19CARled to efficient destruction ofCD19+ 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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