Journal
BLOOD
Volume 119, Issue 24, Pages 5697-5705Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-01-405365
Keywords
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Categories
Funding
- Cancer Center [CA16672]
- Department of Defense [PR064229]
- Burroughs Wellcome Fund
- Cancer Prevention Research Institute of Texas
- CLL Global Research Foundation
- Gillson Longenbaugh Foundation
- Harry T. Mangurian Jr Foundation, Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- Miller Foundation
- Mr and Mrs Joe H. Scales
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- Production Assistance for Cellular Therapies
- Sister Institution Network Fund
- Uehara Memorial Foundation
- William Lawrence and Blanche Hughes Children's Foundation
- Italian Ministry of Health [GR07-5 BO, RO10/07-B-1]
- Italian Ministry of Research and University
- Fondazione Cariplo
- Italian Association for Cancer Research
- EU [GA 222878, 249845]
- Italian Telethon [TELE11/12-12-D2]
- [RO1 (CA124782)]
- [RO1 (CA120956)]
- [RO1 (CA141303)]
- [R33 (CA116127)]
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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 alpha beta 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 alpha or beta 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. (Blood. 2012;119(24):5697-5705)
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