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

被引：151

作者：

Wang, Jinghua ^{[1
,2
]}

Chen, Siyu ^{[3
]}

Xiao, Wei ^{[1
]}

Li, Wende ^{[3
]}

Wang, Liang ^{[4
]}

Yang, Shuo ^{[5
]}

Wang, Weida ^{[1
,2
]}

Xu, Liping ^{[1
,6
]}

Liao, Shuangye ^{[1
,6
]}

Liu, Wenjian ^{[1
,2
]}

Wang, Yang ^{[1
,2
]}

Liu, Nawei ^{[1
,2
]}

Zhang, Jianeng ^{[1
,6
]}

Xia, Xiaojun ^{[1
,6
]}

Kang, Tiebang ^{[1
,6
]}

Chen, Gong ^{[1
]}

Cai, Xiuyu ^{[1
]}

Yang, Han ^{[1
]}

Zhang, Xing ^{[1
]}

Lu, Yue ^{[1
,2
]}

Zhou, Penghui ^{[1
,6
]}

机构：

[1] Collaborat Innovat Ctr Canc Med, State Key Lab Oncol Southern China, Guangzhou 510060, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Canc Ctr, Dept Hematol Oncol, Guangzhou 510060, Guangdong, Peoples R China

[3] Guangdong Key Lab Lab Anim, Guangdong Lab Anim Monitoring Inst, Guangzhou 510663, Guangdong, Peoples R China

[4] Southern Med Univ, Dept Hematol, Zhujiang Hosp, Guangzhou 510282, Guangdong, Peoples R China

[5] Sun Yat Sen Univ, Dept Hematol, Sun Yat Sen Mem Hosp, Guangzhou 510120, Guangdong, Peoples R China

[6] Sun Yat Sen Univ, Dept Expt Res, Canc Ctr, Guangzhou 510060, Guangdong, Peoples R China

来源：

JOURNAL OF HEMATOLOGY & ONCOLOGY | 2018年 / 11卷

关键词：

Acute myeloid leukemia; C-type lectin-like molecule-1; Chimeric antigen receptor; Immunotherapy; Leukemia stem cells; CHIMERIC-ANTIGEN-RECEPTOR; LECTIN-LIKE MOLECULE-1; STEM-CELLS; CANCER-IMMUNOTHERAPY; SAFETY SWITCH; THERAPY; ANTIBODY; SPECIFICITY; EXPRESSION; CYTOTOXICITY;

D O I：

10.1186/s13045-017-0553-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：13

共 46 条

[41] Acute myeloid leukemia stem cells and CD33-targeted immunotherapy [J].