Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

被引:67
作者
Laborda, Eduardo [1 ]
Mazagova, Magdalena [1 ]
Shao, Sida [2 ,3 ]
Wang, Xinxin [1 ]
Quirino, Herlinda [1 ]
Woods, Ashley K. [1 ]
Hampton, Eric N. [1 ]
Rodgers, David T. [1 ]
Kim, Chan Hyuk [1 ,4 ]
Schultz, Peter G. [1 ,2 ,3 ]
Young, Travis S. [1 ]
机构
[1] Calif Inst Biomed Res Calibr, Dept Biol, La Jolla, CA 11119 USA
[2] Scripps Res Inst, Dept Chem, La Jolla, CA 11119 USA
[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 11119 USA
[4] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea
关键词
AML; CAR-T-cell; CLL-1; hematopoiesis; optimization; MODIFIED T-CELLS; IN-VIVO; MICROENVIRONMENT; IMMUNOTHERAPY; SUBPOPULATION; MODULATION; ACTIVATION; RESPONSES; SURVIVAL; DOMAINS;
D O I
10.3390/ijms18112259
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.
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页数:8
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