Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.

Autor: Petrov JC; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA., Wada M; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA. masayuki.wada@icellgene.com., Pinz KG; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA., Yan LE; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA., Chen KH; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA., Shuai X; Department of Hematology West China Hospital, Sichuan University, Chengdu, P.R. China., Liu H; Department of Pathology, Stony Brook Medicine, Stony Brook, NY, 11794, USA., Chen X; Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China., Leung LH; Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China., Salman H; Department of Internal Medicine Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, 11794, USA., Hagag N; Department of Internal Medicine Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, 11794, USA., Liu F; Department of Hematology, Chengdu Military General Hospital, Chengdu, Sichuan, P.R. China., Jiang X; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA., Ma Y; iCell Gene Therapeutics LLC Research & Development Division Long Island High Technology Incubator, 25 Health Science Drive, Stony Brook, NY, 11790, USA. yupo.ma@icellgene.com.; Department of Pathology, Stony Brook Medicine, Stony Brook, NY, 11794, USA. yupo.ma@icellgene.com.; Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. yupo.ma@icellgene.com.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2018 Jun; Vol. 32 (6), pp. 1317-1326. Date of Electronic Publication: 2018 Feb 25.
DOI: 10.1038/s41375-018-0075-3
Abstrakt: Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.
Databáze: MEDLINE
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