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A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR.

Torikai, Hiroki; Reik, Andreas; Liu, Pei-Qi; Zhou, Yuanyue; Zhang, Ling; Maiti, Sourindra; Huls, Helen; Miller, Jeffrey C; Kebriaei, Partow; Rabinovich, Brian; Rabinovitch, Brian; Lee, Dean A; Champlin, Richard E; Bonini, Chiara; Naldini, Luigi; Rebar, Edward J; Gregory, Philip D; Holmes, Michael C; Cooper, Laurence J N.
Blood; 119(24): 5697-705, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22535661
Clinical-grade T cells are genetically modified ex vivo to express a chimeric antigen receptor (CAR) to redirect specificity to a tumor associated antigen (TAA) thereby conferring antitumor activity in vivo. T cells expressing a CD19-specific CAR recognize B-cell malignancies in multiple recipients independent of major histocompatibility complex (MHC) because the specificity domains are cloned from the variable chains of a CD19 monoclonal antibody. We now report a major step toward eliminating the need to generate patient-specific T cells by generating universal allogeneic TAA-specific T cells from one donor that might be administered to multiple recipients. This was achieved by genetically editing CD19-specific CAR(+) T cells to eliminate expression of the endogenous αß T-cell receptor (TCR) to prevent a graft-versus-host response without compromising CAR-dependent effector functions. Genetically modified T cells were generated using the Sleeping Beauty system to stably introduce the CD19-specific CAR with subsequent permanent deletion of α or ß TCR chains with designer zinc finger nucleases. We show that these engineered T cells display the expected property of having redirected specificity for CD19 without responding to TCR stimulation. CAR(+)TCR(neg) T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies.
Selo DaSilva