Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression

Chungyong Han, Su-Jung Sim, Seon-Hee Kim, Rohit Singh, Sunhee Hwang, Yu I. Kim, Sang H. Park, Kwang H. Kim, Don G. Lee, Ho S. Oh, Sangeun Lee, Young H. Kim, Beom K. Choi and Byoung S. Kwon ()
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Chungyong Han: National Cancer Center
Su-Jung Sim: National Cancer Center
Seon-Hee Kim: National Cancer Center
Rohit Singh: National Cancer Center
Sunhee Hwang: Eutilex Institute for Biomedical Research, Eutilex Co., Ltd.
Yu I. Kim: Graduate School of Cancer Science and Policy, National Cancer Center
Sang H. Park: National Cancer Center
Kwang H. Kim: National Cancer Center
Don G. Lee: Biomedicine Production Branch, Research Institute, National Cancer Center
Ho S. Oh: Eutilex Institute for Biomedical Research, Eutilex Co., Ltd.
Sangeun Lee: National Cancer Center
Young H. Kim: Eutilex Institute for Biomedical Research, Eutilex Co., Ltd.
Beom K. Choi: Biomedicine Production Branch, Research Institute, National Cancer Center
Byoung S. Kwon: Eutilex Institute for Biomedical Research, Eutilex Co., Ltd.

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.

Date: 2018
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DOI: 10.1038/s41467-018-02912-x

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