Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients.

Abstract

By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Three patients with metastatic colorectal cancer were then treated with local infusion of the CAR-NK cells. Reduction of ascites generation and a marked decrease in number of tumor cells in ascites samples were observed in the first two patients treated with intraperitoneal infusion of low doses of the CAR-NK cells. The third patient with metastatic tumor sites in the liver was treated with ultrasound-guided percutaneous injection, followed by intraperitoneal infusion of the CAR-NK cells. Rapid tumor regression in the liver region was observed with Doppler ultrasound imaging and complete metabolic response in the treated liver lesions was confirmed by positron emission tomography (PET)- computed tomographic (CT) scanning. Our results highlight a promising therapeutic potential of using RNA CAR-modified NK cells to treat metastatic colorectal cancer.

• Authors: Lin Xiao, Dongzhi Cen, Haining Gan, Yan Sun, Nanqi Huang, Hanzhen Xiong, Qiongmei Jin, Liqun Su, Xuejuan Liu, Kejian Wang, Guangrong Yan, Tianfa Dong, Shangbiao Wu, Pengzhi Zhou, Jinshan Zhang, Weixiang Liang, Junlan Ren, Yaoshu Teng, Can Chen, Xue Hu Xu
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 6 Pg. 1114-1125 (06 05 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 30962163 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• KLRK1 protein, human
• NK Cell Lectin-Like Receptor Subfamily K
• RNA, Messenger
• Receptors, Chimeric Antigen

Topics

• Adoptive Transfer (adverse effects, methods)
• Animals
• Cell Engineering (methods)
• Cell Transplantation (adverse effects, methods)
• Colorectal Neoplasms (mortality, pathology, therapy)
• Cytotoxicity, Immunologic (genetics)
• Feasibility Studies
• Female
• Genetic Vectors
• HCT116 Cells
• Humans
• Killer Cells, Natural (immunology, metabolism, transplantation)
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• NK Cell Lectin-Like Receptor Subfamily K (genetics)
• Pilot Projects
• RNA, Messenger (genetics)
• Receptors, Chimeric Antigen (genetics, immunology, metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays