Treatment of metastatic melanoma is a challenge for clinicians as most agents have failed to demonstrate improved
survival in phase III trials. Despite the immunogenicity of this tumor entity, different immunological interventions
including cytokine therapy, vaccination, biochemotherapy or allogeneic hematopoietic cell transplantation did not
lead to a satisfactory response. However, continuous investigation on the immune mediated rejection of melanoma cells
has led to the development of effective antibodies blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical negative
regulator of the antitumor T-cell response. Based on data from rodent models, the anti-CTLA-4 antibody ipilimumab
was developed into clinical studies where it had encouraging activity in advanced melanoma with unusual response patterns.
As in most immunostimulatory therapies, acute toxicities were severe and clearly mechanism-related. Although
some patients developed signs of autoimmunity, the toxicities were overall manageable and mostly reversible.
This review summarizes different immunotherapeutical approaches against melanoma that have been applied in the past
and focuses on CTLA-4 blockade with respect to its mechanism, clinical effectiveness and immunological side effects.