Open AccessTargeting loss of heterozygosity for cancer-specific immunotherapy
Author(s) -
Michael S. Hwang,
Brian J. Mog,
Jacqueline Douglass,
Alexander H. Pearlman,
Emily HanChung 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
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2022410118
Subject(s) - loss of heterozygosity , biology , immunotherapy , cancer research , cancer , cancer immunotherapy , chimeric antigen receptor , cancer cell , allele , immunology , computational biology , genetics , gene
Significance The lack of viable tumor-specific targets continues to thwart efforts to implement selective anticancer drugs in the clinic. Clonal loss of heterozygosity (LOH) occurs in the great majority of human tumors and represents an irreversible genetic alteration present in cancer cells that unequivocally distinguishes them from normal cells. Here, we report the development of NASCAR (Neoplasm-targeting Allele-Sensing CAR), a platform comprising pairwise chimeric receptors for detecting and targeting LOH events in cancer. As proof-of-concept, we demonstrate specific NASCAR T cell responses in models of HLA LOH in vitro and in vivo. This work lays the foundation for future exploration and exploitation of LOH-mediated vulnerabilities for precision cellular immunotherapy.