期刊
JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 11, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s13045-017-0553-5
关键词
Acute myeloid leukemia; C-type lectin-like molecule-1; Chimeric antigen receptor; Immunotherapy; Leukemia stem cells
资金
- National Key Research and Development Program of China [2016YFA0500304]
- National Nature Science Foundation in China (NSFC) [81572806, 81530081, 81773052, 31571395, 30471976, 81272620]
- Guangzhou Science Technology and Innovation Commission [201607020038]
- Science and technology projects of Guangdong Province [2016A020215086]
- Guangdong Innovative and Entrepreneurial Research Team Program [2016ZT06S638]
- Yangtze River Scholarship [85000-52121100]
- Thousand Talents Plan
- leading talents of Guangdong province program
Background: 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. Methods: 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-zeta signaling domain. We further investigate the function of CLL-1 CAR-T cells. Results: 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. Conclusions: CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.
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