title: Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency.
abstract: The inhibitory anti-CTLA-4 antibody, ipilimumab, dramatically improved survival in a subgroup of metastatic melanoma patients. The majority, however, suffered autoimmune-related adverse events (irAEs), sometimes pathognomonic of acute graft-versus-host-disease (GVHD). This implies that the CTLA-4 blockade is not tumor specific. We make a risky but testable prediction: anti-CTLA-4 therapy may have mechanism similar to that occurring in inherited human CTLA-4 haploinsufficiency. If so, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune-suppressive treatments, but harnessing the immense forces liberated by the anti-CTLA-4 antibody blockade by pretargeting or dose adjustment.
authors: Department of Probability, Alfred Renyi Institute of Mathematics, Hungarian Academy of Sciences, Realtanoda utca 13-15, H-1053 Budapest, Hungary. Electronic address: tiborbakacs@gmail.com.
authors: Tibor
authors: T
authors: Bakacs
authors: The Cambridge Blood, Umbilical Cord Blood Stem Cells for Cell Therapy (Adults/Children), Cultivated RBC Research Initiative (Independent of and separate from the University of Cambridge), Macfarlane Cl. 13, Impington, Cambridge CB24 9LZ, United Kingdom. Electronic address: cambridge-stemcell-cRBC-Res@virginmedia.com.
authors: Jitendra N
authors: JN
authors: Mehrishi
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000209:etiology / Q000517:prevention & control*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics; D002985:Clinical Protocols; D057895:Haploinsufficiency / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D000074324:Ipilimumab; D008545:Melanoma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab
keywords: Anti-CTLA-4 antibody; Ipilimumab, CTLA-4 haploinsufficiency; Targeted immunotherapy