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Int. J. Mol. Sci. 2017, 18(11), 2259; https://doi.org/10.3390/ijms18112259

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

1
Department of Biology, California Institute for Biomedical Research (Calibr), La Jolla, CA 11119, USA
2
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 11119, USA
3
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
*
Authors to whom correspondence should be addressed.
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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Abstract

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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