[Ctla-4 blockade: a new hope for the immunotherapy of malignant melanoma]

Ipilimumab (Yervoy) is a monocLonal antibody designed to block cytotoxic T cell antigen 4 (CTLA-4), an inhibitory receptor of T lymphocytes. This drug is the first to receive US FDAs approval for advanced stage malignant melanoma in the last 13 years. So far, no survival benefit was achieved for this patient group with single drug or combination chemo- and chemo-immunotherapy. In phase II and III trials, up to 15% of patients had melanoma regressions, with a decreased hazard ratio of death of 0.72 compared to the standard chemotherapy with Dacarbazine. The development of Ipilimumab marks a success in deciphering the check-point control on the immune response. Activated T cells over-express CTLA-4 molecule on their surface and become susceptible to its inhibitory effect. CTLA-4 decreases the signaling network derived by antigen recognition of T cells. Alongside of its therapeutic effect, the CTLA-4 blockade enhances autoimmune responses. Severe diarrhea results from toxicity to the colonic mucosa which may eventuate in perforation and, in rare cases, death. Other adverse events of varying severity occur in many patients and include skin eruption, uveitis, endocrinopathies such as thyroiditis and hypophysitis and autoimmune hepatitis. Ipilimumab toxicity is reversible with systemic use of corticosteroids, but the use of TNF inhibitors is sometimes indicated in the absence of resolution. The clinical success of the CTLA-4 blockade motivated intense searches for additional check-point modifiers, such as PD-1 molecule, with encouraging preliminary results. Ipilimumab's entry into the clinic is the opening of a new chapter in the immunotherapy of melanoma in particular, and of cancer, in general.