Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell
Yanran He, Karin Schreiber, Steven P. Wolf, Frank Wen, Catharina Steentoft, Jonathan Zerweck, Madeline Steiner, Preeti Sharma, H. Michael Shepard, Avery Posey, Carl H. June, Ulla Mandel, Henrik Clausen, Matthias Leisegang, Stephen C. Meredith, David M. Kranz, and Hans Schreiber
Find articles by He, Y. in: JCI | PubMed | Google Scholar
Find articles by Schreiber, K. in: JCI | PubMed | Google Scholar
Find articles by Wolf, S. in: JCI | PubMed | Google Scholar
Find articles by Wen, F. in: JCI | PubMed | Google Scholar
Find articles by Steentoft, C. in: JCI | PubMed | Google Scholar
Find articles by Zerweck, J. in: JCI | PubMed | Google Scholar
Find articles by Steiner, M. in: JCI | PubMed | Google Scholar
Find articles by Sharma, P. in: JCI | PubMed | Google Scholar
Find articles by Shepard, H. in: JCI | PubMed | Google Scholar
Find articles by Posey, A. in: JCI | PubMed | Google Scholar
Find articles by June, C. in: JCI | PubMed | Google Scholar
Find articles by Mandel, U. in: JCI | PubMed | Google Scholar
Find articles by Clausen, H. in: JCI | PubMed | Google Scholar
Find articles by Leisegang, M. in: JCI | PubMed | Google Scholar
Find articles by Meredith, S. in: JCI | PubMed | Google Scholar
Find articles by Kranz, D. in: JCI | PubMed | Google Scholar
Find articles by Schreiber, H. in: JCI | PubMed | Google Scholar
Published December 5, 2019 - More info
JCI Insight. 2019;4(23):e135306. https://doi.org/10.1172/jci.insight.135306.
© 2019 American Society for Clinical Investigation
Related article:
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 Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced 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.
Authors
Yanran He, Karin Schreiber, Steven P. Wolf, Frank Wen, Catharina Steentoft, Jonathan Zerweck, Madeline Steiner, Preeti Sharma, H. Michael Shepard, Avery Posey, Carl H. June, Ulla Mandel, Henrik Clausen, Matthias Leisegang, Stephen C. Meredith, David M. Kranz, Hans Schreiber
Original citation: JCI Insight. 2019;4(21):e130416. https://doi.org/10.1172/jci.insight.130416
Citation for this corrigendum: JCI Insight. 2019;4(23):e135306. https://doi.org/10.1172/jci.insight.135306
The authors’ conflict-of-interest statement was not included in the manuscript. The HTML and PDF versions have been updated to include this information. The correct statement is also below.
Conflict of interest: HS and YH are 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’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.
The authors regret the error.
