气候变化领域集成服务门户(CCPortal): Targeting loss of heterozygosity for cancer-specific immunotherapy

CCPortal

DOI	10.1073/pnas.2022410118
	Targeting loss of heterozygosity for cancer-specific immunotherapy
	Hwang M.S.; Mog B.J.; Douglass J.; Pearlman A.H.; Hsiue E.H.-C.; Paul S.; DiNapoli S.R.; Konig M.F.; Pardoll D.M.; Gabelli S.B.; Bettegowda C.; Papadopoulos N.; Vogelstein B.; Zhou S.; Kinzler K.W.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by “inverting” the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Loss of heterozygosity \| human leukocyte antigen \| cell engineering \| cancer immunotherapy \| chimeric antigen receptor
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180147
作者单位	Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; HHMI, Chevy Chase, MD 20815, United States; Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School ofMedicine, Baltimore, MD 21287, United States; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Oncology, JohnsHopkins University School of Medicine, Baltimore, MD 21287, United States; Division of Rheumatology, Department of Medicine, Johns Hopkins University School ofMedicine, Baltimore, MD 21224, United States; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, United States; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Medicine, Johns Hopkins University Scho...
推荐引用方式 GB/T 7714	Hwang M.S.,Mog B.J.,Douglass J.,et al. Targeting loss of heterozygosity for cancer-specific immunotherapy[J],2021,118(12).
APA	Hwang M.S..,Mog B.J..,Douglass J..,Pearlman A.H..,Hsiue E.H.-C..,...&Kinzler K.W..(2021).Targeting loss of heterozygosity for cancer-specific immunotherapy.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Hwang M.S.,et al."Targeting loss of heterozygosity for cancer-specific immunotherapy".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).