@article{79b9ea61c7774e5398724b9052e19135,
title = "Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell",
abstract = "Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tnglycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CARtransduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely.",
author = "Yanran He and Karin Schreiber and Wolf, \{Steven P.\} and Frank Wen and Catharina Steentoft and Jonathan Zerweck and Madeline Steiner and Preeti Sharma and \{Michael Shepard\}, H. and Avery Posey and June, \{Carl H.\} and Ulla Mandel and Henrik Clausen and Matthias Leisegang and Meredith, \{Stephen C.\} and Kranz, \{David M.\} and Hans Schreiber",
note = "This study was supported by NIH grants R01-CA22677, R01-CA37156, and R01-CA226983; the Gerald O. Mann Foundation/Harriet and Allan Wulfstat, Trustees; a gift from Janet D. Rowley to KS and HS; the Cancer Research Foundation; the Lundbeck Foundation (R221-2016-438); L{\ae}ge Sofus Carl Emil Friis og hustru Olga Doris Friis{\textquoteright} Legat; and the Danish National Research Foundation (DFF-4004-00397B). The frequency and the types of COSMC mutations among different cancer types in Figure 8 were generated based on data acquired from the Cancer Genome Atlas (TCGA) research network: https://www.cancer. gov/tcga. We thank Boris Engels and Cecelia Lai for helping with CAR construction and transduction, and Patrick Moore for helping with quantifying glycopeptides, and Eric Seidel for his advice on the CRIS-PR-Cas9 system. We also thank Sandra J. Gendler for her advice on MUC1. inventors of intellectual property (IP) surrounding 237Ab-derived CARs. DMK has ownership interest in Bellicum Pharmaceuticals, Agenus Inc., and Jounce Therapeutics and is a consultant/advisory board member for AbbVie. DMK and PS are coinventors of the IP surrounding 237Ab-derived CARs. CHJ reports research funding from Novartis, and he is a scientific founder of Tmunity Therapeutics, for which he has founder{\textquoteright}s stock but no income. CHJ also works under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research, Inc, and he is an inventor of IP licensed by the University of Pennsylvania to Novartis. ADP reports research funding from Tmunity Therapeutics around the clinical development of 5E5-CART cells and has IP licensed to Novartis for CART cell therapy as well as gene therapy. HC, CS, and UM are coinventors of IP surrounding 5E5Ab-derived CARs licensed by the University of Copenhagen to Novartis.",
year = "2019",
month = oct,
day = "17",
doi = "10.1172/jci.insight.130416",
language = "English (US)",
volume = "4",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "21",
}