Anticancer agent-ipilimumab.

More than 50 cancer vaccines are currently in clinical trials. They stimulate the immune system to attack cancerous cells, but many have proved disappointing. Many tumour cells produce self-antigens that mean they are not destroyed by the immune system, allowing the tumour to grow unchecked. Numerous pathways exist that ensure the body tolerates these self-antigens, and Medarex is developing ipilimumab, which is designed to target the immune system as a whole, and also its interaction with the tumour. It is being co-developed with Bristol-Myers Squibb.

Ipilimumab is a fully human immunoglobulin G1 anti-CTLA-4 monoclonal antibody. Blocking CTLA-4 can be used to enhance antitumour responses, either on its own or in combination with cancer vaccines to direct immune responses towards the target antigens, improving their activity. Several clinical trials have been carried out to investigate its potential. For example, a Phase I trial was run in 17 patients with progressive, unresectable malignant melanoma 1 They were given a single intravenous dose of 3mg/kg ipilimumab over 90 minutes. Plasma levels of the antibody were maintained for up to four months, and treatment was well tolerated. Two patients had a partial response, including the resolution of three soft tissue masses, and a reduction in a lung mass of more than 50%.

Another trial was run in 19 melanoma patients with high risk resected stage III/IV melanoma" They had been immunised with three tumour antigen epitope peptides from gp1 00, MART-1 and tyrosinase, and were then given 0.3, 1 or 3 mg/kg ipilimumab every four weeks for six months, and then every 1 2 weeks for a further six months. Three of the patients given the highest dose developed grade 3 diarrhoea, and the maximum tolerated dose for this schedule was thus determined to be 1 mg/kg. Eight of the patients showed evidence of autoimmunity, three of whom had disease relapse. Of the other 11, the disease relapsed in nine of them. Median time to relapse was 18 months.

A multicentre randomised Phase II trial has been carried out in 72 patients with stage IV melanoma.' They were given 3mg/kg ipilimumab once a month for four months, either alone or in combination 250 mg/m2 dacarbazine, given for five days a month for four months. Two deaths were possibly related to ipilimumab, but two given the drug as monotherapy had a partial response and there were four cases of stable disease in this group. For those given the combination, there were two complete responses, four partial responses, and four achieved stable disease. The mean progression-free survival rate was 82 days for monotherapy and 99 for the combination. Phase III trials are under way for metastatic melanoma; it is also being investigated, either alone or in combination with cancer vaccines, for colon, prostate, ovarian and pancreatic cancers, plus NSCLC, lymphoma and synovial sarcoma.