Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer.

Ipilimumab (Yervoy, developed by Medarex and Bristol-Myers Squibb) is a fully\r\nhuman monoclonal IgG1κ antibody against the cytotoxic T-lymphocyte antigen-4\r\n(CTLA-4), an immune-inhibitory molecule expressed in activated T cells and in\r\nsuppressor T regulatory cells. Interaction of the monoclonal antibody with CTLA-4\r\nblocks inhibitory signals generated through this receptor and enhances T cell\r\nactivation, leading to increased antitumor responses. Ipilimumab has been\r\napproved by FDA in March 2011 as monotherapy (3mg/kg every 3 weeks for 4 doses)\r\nfor the treatment of advanced (unresectable or metastatic) melanoma both in\r\npre-treated or chemotherapy naïve patients. Four months later, ipilimumab has\r\nreceived a rapid approval by the European Commission, after a positive opinion\r\nfrom the Committee for Medicinal Products for Human Use. However, the indication \r\nin the EU is limited to previously-treated patients with advanced melanoma.\r\nIpilimumab is the first agent that has demonstrated to improve overall survival\r\nin patients with metastatic melanoma, which has a very poor prognosis, in\r\nrandomized phase III clinical trials. The patterns of tumour response to\r\nipilimumab differ from those observed with cytotoxic chemotherapeutic agents,\r\nsince patients may have a delayed yet durable response and obtain long-term\r\nsurvival benefit despite an initial tumour growth. The major draw-back of\r\nipilimumab is the induction of immune-related adverse effects; the latter can be \r\nlife-threatening, unless promptly managed with immunosuppressive agents (most\r\nfrequently corticosteroids) according to specific guidelines. Further development\r\nof ipilimumab includes its use in the neoadjuvant or adjuvant high-risk melanoma \r\nsetting and for the treatment of other refractory and advanced solid tumours,\r\neither as single agent or in combination with additional immunostimulating agents\r\nor molecularly targeted therapies.