Clinical Development of the Anti-CTLA-4 Antibody Tremelimumab

Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.