CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia

• Published in: Journal of hematology and oncology Vol. 11; no. 1; pp. 7 - 13
• Main Authors: Wang, Jinghua, Chen, Siyu, Xiao, Wei, Li, Wende, Wang, Liang, Yang, Shuo, Wang, Weida, Xu, Liping, Liao, Shuangye, Liu, Wenjian, Wang, Yang, Liu, Nawei, Zhang, Jianeng, Xia, Xiaojun, Kang, Tiebang, Chen, Gong, Cai, Xiuyu, Yang, Han, Zhang, Xing, Lu, Yue, Zhou, Penghui
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.01.2018; BioMed Central; BMC
• Subjects: Acute myelocytic leukemia; Acute myeloid leukemia; C-type lectin-like molecule-1; Care and treatment; Chimeric antigen receptor; Genetic aspects; Health aspects; Immunotherapy; Leukemia stem cells; Physiological aspects; T cells; China; C-type lectin-like molecule-1; Chimeric antigen receptor; Acute myeloid leukemia; Immunotherapy; Leukemia stem cells
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-017-0553-5

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1 cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.