Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Immunobiology. 2015 May;220(5):624-5. doi: 10.1016/j.imbio.2014.11.019. Epub 2014 Dec 6.

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.

Keywords: Anti-CTLA-4 antibody; Ipilimumab, CTLA-4 haploinsufficiency; Targeted immunotherapy.

MeSH terms

  • Animals
  • Antibodies, Blocking / adverse effects
  • Antibodies, Blocking / therapeutic use*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use*
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / prevention & control*
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / genetics
  • Clinical Protocols
  • Haploinsufficiency / immunology
  • Homeostasis
  • Humans
  • Immunotherapy / adverse effects
  • Immunotherapy / methods*
  • Ipilimumab
  • Melanoma / complications
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Skin Neoplasms / complications
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ipilimumab