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

Journal of Hematology & Oncology

Shuo Yang¹  Liang Wang²  Wende Li³  Siyu Chen³  Yue Lu⁴  Jinghua Wang⁴  Xing Zhang⁴  Penghui Zhou⁴  Tiebang Kang⁴  Wenjian Liu⁴  Jianeng Zhang⁴  Xiaojun Xia⁴  Wei Xiao⁴  Shuangye Liao⁴  Yang Wang⁴  Han Yang⁴  Weida Wang⁴  Gong Chen⁴  Liping Xu⁴  Nawei Liu⁴  Xiuyu Cai⁴ 

[1] Department of Hematology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University;Department of Hematology, Zhujiang Hospital of Southern Medical University;Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals;State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine;

关键词: Acute myeloid leukemia;    C-type lectin-like molecule-1;    Chimeric antigen receptor;    Immunotherapy;    Leukemia stem cells;   

DOI  :  10.1186/s13045-017-0553-5

来源: DOAJ

【 摘 要 】

Abstract 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-ζ 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.

【 授权许可】

Unknown