Targeting loss of heterozygosity for cancer-specific immunotherapy

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article numbere2022410118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 23 2021


  • Loss of heterozygosity | human leukocyte antigen | cell engineering | cancer immunotherapy | chimeric antigen receptor

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Targeting loss of heterozygosity for cancer-specific immunotherapy'. Together they form a unique fingerprint.

Cite this