Targeting loss of heterozygosity for cancer-specific immunotherapy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 12; pp. 1 - 10
• Main Authors: Hwang, Michael S., Mog, Brian J., Douglass, Jacqueline, Pearlman, Alexander H., Hsiue, Emily Han-Chung, Paul, Suman, DiNapoli, Sarah R., Konig, Maximilian F., Pardoll, Drew M., Gabelli, Sandra B., Bettegowda, Chetan, Papadopoulos, Nickolas, Vogelstein, Bert, Zhou, Shibin, Kinzler, Kenneth W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.03.2021
• Series: Inaugural Article
• Subjects: Alleles; Antigens, Neoplasm - immunology; Biological Sciences; Biomarkers, Tumor; Cell- and Tissue-Based Therapy; HLA Antigens - genetics; HLA Antigens - immunology; Humans; Immunotherapy - methods; Immunotherapy, Adoptive; INAUGURAL ARTICLE; Loss of Heterozygosity; Molecular Targeted Therapy - adverse effects; Molecular Targeted Therapy - methods; Neoplasms - etiology; Neoplasms - therapy; Single-Chain Antibodies - pharmacology; Single-Chain Antibodies - therapeutic use; cell engineering; chimeric antigen receptor; loss of heterozygosity; human leukocyte antigen; cancer immunotherapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2022410118

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.