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

Department of Biology, California Institute for Biomedical Research (Calibr), La Jolla, CA 11119, USA
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 11119, USA
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(11), 2259;
Received: 4 October 2017 / Revised: 23 October 2017 / Accepted: 24 October 2017 / Published: 27 October 2017
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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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. View Full-Text
Keywords: AML; CAR-T-cell; CLL-1; hematopoiesis; optimization AML; CAR-T-cell; CLL-1; hematopoiesis; optimization

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Laborda, E.; Mazagova, M.; Shao, S.; Wang, X.; Quirino, H.; Woods, A.K.; Hampton, E.N.; Rodgers, D.T.; Kim, C.H.; Schultz, P.G.; Young, T.S. Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia. Int. J. Mol. Sci. 2017, 18, 2259.

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