This symposium has been developed to provide clinicians with the most up-to-date clinical data and knowledge regarding the practical, clinical aspects of using CTLA-4 blockade immunotherapy for treating melanoma. CTLA-4 blockade is an entirely new class of therapy and is quite different from other “targeted therapies” in many aspects, beginning with its mechanism of action. Anti-CTLA-4 therapy is also associated with some novel efficacy endpoint measurements, unique patient response patterns and immune-related but manageable adverse events, which also help guide therapy as predictors of outcomes. The clinical benefits, efficacy and safety of anti-CTLA-4 therapy for melanoma are reviewed in a practical, “how to use this therapy” instructional and interactive symposium format.

A faculty consisting of scientific and clinical melanoma experts from the USA and Europe will present, review, and discuss how to employ anti-CTLA-4 therapy into their treatment strategies for melanoma. They will address the usage of this novel immunotherapy from several perspectives that are unique to this class of agents. The faculty will explain the science behind anti-CTLA-4 therapy, and how it acts upon the immune system, not on the malignancy, review the key clinical data to date with both anti-CTLA-4 drugs, review the unique adverse events -- immune-related Adverse Events (irAEs) caused by anti-CTLA-4’s effect on the immune system, but more importantly how to successfully manage these irAEs, and then review the increasingly important biomarkers used in conjunction with anti-CTLA-4 therapy for treating melanoma.

In the USA, the estimated incidence of melanoma for 2009 was 68,720 people with an expected 8,650 deaths that year from this malignancy. The incidence of melanoma continues to increase as a result of higher exposure to ultraviolet light. The incidence of melanoma in populations of Caucasians in other countries is generally similar to that in the USA as a percentage of the population, and in most countries the incidence is increasing annually by a few percent.

Dacarbazine is currently the only cytotoxic agent approved for use in the USA for advanced melanoma. And interleukin-2 (IL-2) and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the USA. Despite the commercial availability of numerous agents to treat melanoma, standard therapy for this malignancy today is considered experimental. The treatment guidelines of the National Comprehensive Cancer Network specify to use an experimental therapy by enrolling a patient in a clinical trial for treatment of melanoma.

Historically, there have been several attempts to utilize immunotherapy to treat any of a number of malignancies. William Coley in 1890, administered bacterial products for treating advanced malignancies and demonstrated significant responses. However, the widespread use of immunotherapy as an anti-cancer therapy emerged when IL-2 demonstrated some efficacy in the 1980’s. Immunotherapy until now, however, has had only limited success for treating patients with melanoma.

The limitations of effectively utilizing immunotherapy for melanoma are derived from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. Melanoma, for example, inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. Several novel immunotherapies are currently in clinical testing for melanoma. These include human antibodies that block Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and other immunotherapeutic agents affecting different components of the immune system. CTLA-4 blockade with an antibody is the immunotherapy therapy for melanoma that is furthest along in clinical development.

Currently, there are two fully human anti-CTLA4 MAbs that have been extensively evaluated in the clinic for the treatment of melanoma. These two MAbs have somewhat different pharmacokinetic and pharmacodynamic properties.

Tremelimumab
One of these two MAbs is tremelimumab, a fully human immunoglobulin G-2 anti-CTLA4 MAb. Tremelimumab has been studied in two large clinical trials in patients with metastatic melanoma: a Phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a Phase II trial of tremelimumab in previously treated patients with advanced melanoma. However, in 2008 the clinical development of tremelimumab for the treatment of melanoma was halted. But in January 2010 it was announced that a new clinical development program for tremelimumab for advanced melanoma is scheduled to begin in 2010 or 2011.

Ipilimumab
The other anti-CTLA-4 MAb is Ipilimumab (MDX-010; Medarex Inc. / Bristol-Myers Squibb) an immunoglobulin G-1 anti-CTLA4 MAb. There are numerous completed and ongoing Phase II and Phase III trials with ipilimumab for melanoma. Ipilimumab has been used as monotherapy or combined with other therapies, including cytokines, vaccines and chemotherapy. Phase III registration trials for ipilimumab in melanoma are complete and it is possible the US Food and Drug Administration might approve ipilimumab for treating melanoma in 2010 or 2011.