There has been a long fascination with immunizing against
cancer in general and against
melanoma in particular. The earliest
melanoma vaccines were formulated from autologous or allogeneic
melanoma cells. Subsequently, molecularly defined
vaccines made from
proteins,
peptides, or
gangliosides were developed and, recently,
DNA-based
vaccines are currently being tested. Randomized trials using allogeneic
melanoma cells/lysates or
gangliosides have not demonstrated a clinical benefit, although in some trials, clinical benefit was seen in large subsets. On the other hand, some clinical trials indicated that vaccine therapy could be associated with a poorer survival. There are several mechanisms now identified by which
melanoma cells can avoid detection by T cells, such as loss of expression of
antigen or
human leukocyte antigen (HLA) molecules, and
tumor vascular adhesion molecules. Also, mediators of immune tolerance are now well-characterized such as regulatory T cells and inhibitory
cytokines secreted by
melanoma cells. Future approaches for immunizing against
melanoma will have to incorporate strategies to overcome these barriers. Strategies being tested include depletion of regulatory T cells, immunization in the setting of
lymphopenia, and blockade of T-cell inhibitory molecules such as CTLA-4. Once a relevant clinical response can be induced, it should be possible to develop validated immunoassays that will direct future
melanoma vaccine development.