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.
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