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

Blood - Tập 119 Số 24 - Trang 5697-5705 - 2012
Hiroki Torikai1, Andreas Reik2, Pei-Qi Liu2, Yuanyue Zhou2, Ling Zhang1, Sourindra N. Maiti1, Helen Huls1, Jeffrey C. Miller2, Partow Kebriaei3, Brian Rabinovitch1, Dean A. Lee1,4, Richard E. Champlin3, Chiara Bonini5, Luigi Naldini6, Edward J. Rebar2, Philip D. Gregory2, Michael C. Holmes2, Laurence J.N. Cooper1,4
1Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX
2Sangamo BioSciences Inc., Richmond, CA;
3Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
4The University of Texas Graduate School of Biomedical Sciences, Houston, TX; and
5Experimental Hematology Unit, Division of Regenerative Medicine, Gene Therapy and Stem Cells, Program in Immunology and Bio-immunotherapy of Cancer, and
6San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy

Tóm tắt

Abstract 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 αβ 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 β 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+TCRneg T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies.

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Blood

Tập 119 Số 24

5697-5705

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