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Targeting loss of heterozygosity for cancer-specific immunotherapy

Proc Natl Acad Sci U S A. 2021-03; 
Michael S Hwang, Brian J Mog, Jacqueline Douglass, Alexander H Pearlman, Emily Han-Chung Hsiue, Suman Paul, Sarah R DiNapoli, Maximilian F Konig, Drew M Pardoll, Sandra B Gabelli, Chetan Bettegowda, Nickolas Papadopoulos, Bert Vogelstein, Shibin Zhou, Kenneth W Kinzler
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DNA Sequencing clone GAP.A3 for A3 (102)]. Hybridomas for both clones were commercially acquired (American Type Culture Collection [ATCC]), and hybridoma sequences were obtained by next-generation sequencing (GenScript). Get A Quote

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 can... More

关键词

cancer immunotherapy, cell engineering, chimeric antigen receptor, human leukocyte antigen, loss of heterozygosity