Oncotarget

Research Papers:

Gene-modified NK-92MI cells expressing a chimeric CD16-BB-ζ or CD64-BB-ζ receptor exhibit enhanced cancer-killing ability in combination with therapeutic antibody

Ying Chen, Fengtao You, Licui Jiang, Jialu Li, Xuejun Zhu, Yangyi Bao, Xiang Sun, Xiaowen Tang, Huimin Meng, Gangli An, Bozhen Zhang & Lin Yang _

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Oncotarget. 2017; 8:37128-37139. https://doi.org/10.18632/oncotarget.16201

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Abstract

Ying Chen1,2, Fengtao You1,2,3,4, Licui Jiang3,4, Jialu Li1,2, Xuejun Zhu5, Yangyi Bao6, Xiang Sun6, Xiaowen Tang2,7, Huimin Meng1,2, Gangli An1,2, Bozhen Zhang3,4, Lin Yang1,2,3

1The Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu, PR China

2Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, PR China

3Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, Jiangsu, PR China

4Persongen BioTherapeutics Co., Ltd., Suzhou, Jiangsu, PR China

5Division of Hematology, Department of Medicine, Jiangsu Provincial Traditional Chinese Medical Hospital, Nanjing, Jiangsu Province, PR China

6Binhu Hospital, The First People’s Hospital of Hefei Group, Hefei, Anhui, PR China

7Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China

Correspondence to:

Lin Yang, email: yanglin@suda.edu.cn

Keywords: NK-92MI, chimeric CD16/CD64-BB-ζ receptor, therapeutic antibody

Received: October 07, 2016     Accepted: March 04, 2017     Published: March 15, 2017

ABSTRACT

Natural killer (NK) cells play a pivotal role in monoclonal antibody-mediated immunotherapy through the antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. NK-92MI is an interleukin-2 (IL-2)-independent cell line, which was derived from NK-92 cells with superior cytotoxicity toward a wide range of tumor cells in vitro and in vivo. Nonetheless, the Fc-receptor (CD16) that usually mediates ADCC is absent in NK-92 and NK-92MI cells. To apply NK-92MI cell-based immunotherapy to cancer treatment, we designed and generated two chimeric receptors in NK-92MI cells that can bind the Fc portion of human immunoglobulins. The construct includes the low-affinity Fc receptor CD16 (158F) or the high-affinity Fc receptor CD64, with the addition of the CD8a extracellular domain, CD28 transmembrane domains, two costimulatory domains (CD28 and 4-1BB), and the signaling domain from CD3ζ. The resulting chimeric receptors, termed CD16-BB-ζ and CD64-BB-ζ, were used to generate modified NK-92MI cells expressing the chimeric receptor, which were named NK-92MIhCD16 and NK-92MIhCD64 cells, respectively. We found that NK-92MIhCD16 and NK-92MIhCD64 cells significantly improved cytotoxicity against CD20-positive non-Hodgkin’s lymphoma cells in the presence of rituximab. These results suggest that the chimeric receptor-expressing NK-92MI cells may enhance the clinical responses to currently available anticancer monoclonal antibodies.


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