Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice

Cell Research
Xuexiang DuPan Zheng

Abstract

Anti-CTLA-4 monoclonal antibodies (mAbs) confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAE). Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with very mild irAE under the same conditions. The irAE corresponded to systemic T cell activation and resulted in reduced ratios of regulatory to effector T cells (Treg/Teff) among autoreactive T cells. Using mice that were either homozygous or heterozygous for the human allele, we found that the irAE required bi-allelic engagement, while CITE only required monoallelic engagement. As with the immunological distinction for monoallelic vs bi-allelic engagement, we found that bi-allelic engagement of the Ctla4 gene was necessary for preventing conversion ...Continue Reading

References

Mar 22, 1996·Science·D R LeachJ P Allison
Jan 18, 2003·Immunity·Booki MinWilliam E Paul
Jun 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Giao Q PhanSteven A Rosenberg
Mar 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Booki MinWilliam E Paul
Nov 23, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ajay V MakerSteven A Rosenberg
May 30, 2006·Advances in Immunology·Alan J KormanJames P Allison
May 29, 2007·Trends in Immunology·Yang Liu, Pan Zheng
Oct 8, 2008·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Xing ChangYang Liu
Dec 5, 2008·Cancer Immunology, Immunotherapy : CII·Ilyssa O GordonThomas F Gajewski
Jun 8, 2010·The New England Journal of Medicine·F Stephen HodiWalter J Urba
Jan 9, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Antoni RibasAxel Hauschild
May 22, 2013·Proceedings of the National Academy of Sciences of the United States of America·Tomoyuki YamaguchiShimon Sakaguchi
Jun 4, 2013·The New England Journal of Medicine·Jedd D WolchokMario Sznol
Jun 19, 2013·The Oncologist·Leslie A FecherJeffrey S Weber
Jul 31, 2013·The Journal of Experimental Medicine·Yannick BulliardJennifer L Brogdon
Feb 11, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Dirk SchadendorfJedd D Wolchok
Apr 19, 2015·Annals of Oncology : Official Journal of the European Society for Medical Oncology·T W ChenA R Hansen
Jun 2, 2015·The New England Journal of Medicine·James LarkinJedd D Wolchok
Mar 18, 2016·The New England Journal of Medicine·Ranjit NairSuresh G Nair
Apr 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·Katrin KlockeKajsa Wing
Jul 2, 2016·JAMA Oncology·Claire F FriedmanMichael A Postow
Dec 31, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Tomasz M BeerWinald Gerritsen
Sep 12, 2017·The New England Journal of Medicine·Jeffrey WeberUNKNOWN CheckMate 238 Collaborators

❮ Previous
Next ❯

Citations

Mar 30, 2018·Cell Research·Jonathan Pol, Guido Kroemer
Feb 14, 2020·Science Translational Medicine·Candice R GurbatriTal Danino
May 29, 2019·Journal of Clinical Neuromuscular Disease·Carlen YuenKourosh Rezania
May 1, 2020·Frontiers in Immunology·Qiuxia QuBinfeng Lu
Aug 28, 2020·Frontiers in Immunology·Shin Foong Ngiow, Arabella Young
Nov 7, 2019·Cell Research·UNKNOWN Cell Research Editorial Team
Oct 15, 2019·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Charles BrownKeith E Steele
Dec 12, 2018·The Journal of Clinical Investigation·Jarushka NaidooFranco D'Alessio
Dec 12, 2018·Journal of Diabetes Research·Tong ZhouGuixia Wang
Oct 23, 2019·Signal Transduction and Targeted Therapy·Ziying ZhangYongguang Tao
Jul 14, 2019·Cell Research·Amnon Altman, Kok-Fai Kong
May 7, 2020·Journal of Hematology & Oncology·Jifeng YuWenzhi Tian
Mar 7, 2020·Frontiers in Immunology·Rachael M ZemekW Joost Lesterhuis
Apr 16, 2020·Cancers·Marit J van ElsasSjoerd H van der Burg
Nov 22, 2020·Journal for Immunotherapy of Cancer·Karen KellyJames L Gulley
Dec 5, 2018·Cancer Immunology Research·Arabella YoungJeffrey A Bluestone
Oct 23, 2020·Journal of Personalized Medicine·Vincenzo QuagliarielloNicola Maurea
Oct 11, 2020·Signal Transduction and Targeted Therapy·Ziying ZhangYongguang Tao
Feb 23, 2021·Frontiers in Cardiovascular Medicine·Shirley XuSaraswati Pokharel
Apr 26, 2021·Macromolecular Bioscience·Ziwen DaiZhigang Wang
May 1, 2021·Antibody Therapeutics·Jing ZhangPengfei Zhou
May 11, 2021·Frontiers in Immunology·Nina B HorowitzJohn B Sunwoo
Jun 5, 2021·International Journal of Cancer. Journal International Du Cancer·Wenfeng LiuWenbo Zhu
Oct 1, 2021·Journal for Immunotherapy of Cancer·Hsin-Yu LiuAmnon Altman
Dec 8, 2021·Frontiers of Medicine·Hongyun ZhaoRui-Hua Xu

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
FACS
PCR
targeted mutation
ELISA
Assay

Software Mentioned

Excel
GraphPad Prism
R

Related Concepts

Related Feeds

Cancer Vaccines

Cancer vaccines are vaccines that either treat existing cancer or prevent development of a cancer.