Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice

Cancer Research
Xiaojun LiuYangbing Zhao

Abstract

Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissues that express it at physiologic levels. A CAR-expressing T-cell panel was generated with target antigen affinities varying over three orders of magnitude. High-affinity cells recognized target expressed at any level, including at levels in normal cells that were undetectable by flow cytometry. Affinity-tuned cells exhibited robust antitumor efficacy similar to high-affinity cells, but spared normal cells expressing physiologic target levels. The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach.

References

May 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·P CarterH M Shepard
Mar 18, 2005·Proceedings of the National Academy of Sciences of the United States of America·Pablo A GonzálezAlexis M Kalergis
Jul 30, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Román Peréz-Soler, Leonard Saltz
May 2, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Cor H J LamersEgbert Oosterwijk
Aug 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christoph A RitterCarlos L Arteaga
Oct 20, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yangbing ZhaoRichard A Morgan
Feb 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·Carmine CarpenitoCarl H June
Sep 3, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Martin A CheeverLynn M Matrisian
Feb 25, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Richard A MorganSteven A Rosenberg
Mar 31, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Daphné A SchmidNathalie Rufer
Dec 16, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maria R ParkhurstSteven A Rosenberg
Aug 13, 2011·The New England Journal of Medicine·David L PorterCarl H June
Aug 16, 2011·Human Gene Therapy·David M BarrettStephan A Grupp
Nov 4, 2011·The New England Journal of Medicine·Antonio Di StasiMalcolm K Brenner
Sep 14, 2012·Frontiers in Immunology·Salvatore Valitutti
Feb 5, 2013·Journal of Immunotherapy·Richard A MorganSteven A Rosenberg
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Shi ZhongMichelle Krogsgaard
Apr 27, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael HudecekStanley R Riddell
Oct 22, 2013·Nature Biotechnology·Christian S Hinrichs, Nicholas P Restifo
Jun 13, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edmund K MoonSteven M Albelda

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Citations

Mar 22, 2016·Journal of Immunology Research·Yelei GuoWeidong Han
Dec 26, 2015·Trends in Pharmacological Sciences·Daniel T Harris, David M Kranz
Mar 11, 2016·Current Opinion in Immunology·Eugene A ZhukovskyMarcela V Maus
May 28, 2016·Molecular Therapy Oncolytics·Daniel Abate-Daga, Marco L Davila
Jun 15, 2016·Journal of Immunology Research·Hilde AlmåsbakMohan C Vemuri
Aug 23, 2016·Expert Review of Clinical Immunology·Andreas A Hombach, Hinrich Abken
May 11, 2016·Journal of Cellular Physiology·Albert T GacerezCharles L Sentman
Aug 24, 2016·Nature Reviews. Cancer·Andrew D FesnakBruce L Levine
Nov 12, 2016·Frontiers in Pharmacology·Tetsuro SasadaYuki Fujimoto
Dec 28, 2016·Cell Research·Laura A Johnson, Carl H June
Jan 29, 2016·Journal of the National Cancer Institute·Hanren DaiWeidong Han
Mar 28, 2017·Laboratory Investigation; a Journal of Technical Methods and Pathology·Robert SacksteinSteven R Barthel
Mar 23, 2017·Pharmacology & Therapeutics·Jason Lohmueller, Olivera J Finn
May 10, 2017·Proceedings of the National Academy of Sciences of the United States of America·Udupi A RamagopalSteven C Almo
Jun 27, 2017·Cancer Letters·Ju YangBaorui Liu
Jun 7, 2017·Expert Opinion on Biological Therapy·Robyn A A Oldham, Jeffrey A Medin
Dec 15, 2017·Journal of Immunotherapy·Gemma L OwensRichard Harrop
Jan 10, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shivani Srivastava, Stanley R Riddell
Dec 1, 2017·Current Opinion in Pediatrics·Liora M SchultzCrystal Mackall
Oct 19, 2017·Protein Engineering, Design & Selection : PEDS·Casey K HuaMargaret E Ackerman
Jan 10, 2018·Frontiers in Immunology·Yuedi WangYiwei Chu
Jan 21, 2017·Scientific Reports·Alexandre JuilleratLaurent Poirot
Oct 3, 2018·PLoS Biology·Frédéric ThomasBeata Ujvari
Oct 15, 2018·Journal of Cellular Physiology·Hamid Reza MirzaeiJamshid Hadjati
Feb 10, 2019·Journal of Clinical Medicine·Susanne HofmannMichael Schmitt
Mar 5, 2019·Archives of Pharmacal Research·Young-Ho Lee, Chan Hyuk Kim
Feb 5, 2019·Frontiers in Immunology·Alka DwivediRahul Purwar
Dec 12, 2018·Annual Review of Immunology·Sonia GuedanCarl H June
Jul 30, 2019·Immunological Reviews·Zachary WalshM Eric Kohler
Jul 30, 2019·Immunological Reviews·Smita S Chandran, Christopher A Klebanoff
Jul 30, 2019·Immunological Reviews·David AkhavanChristine E Brown
Sep 26, 2019·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Emiliano RoselliDaniel Abate-Daga

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