This review summarises the evolution of recent major advances in cancer 
immunotherapy, using metastatic melanoma as a model. The first true clinical 
progress with immunotherapy developed from the application of recombinant DNA 
technology for the large scale production of immunostimulant cytokines. Clinical 
trials demonstrated that the systemic administration of recombinant high-dose 
bolus intravenous interleukin-2 (IL-2; 720 000 IU/kg every 8 hours) mediated 
objective tumour progression in 20% of patients with metastatic renal cancer and 
in 17% of patients with metastatic melanoma, with complete responses of 9% and 
7%, respectively. The use of adoptive immunotherapy (the transfer of immune 
cells with anti-tumour activity to the tumour-bearing host) focused interest on 
T lymphocyte-mediated tumour recognition. Clinical trials described the systemic 
administration of lymphokine activated killer (LAK) cells and subsequently 
tumour infiltrating lymphocytes (TIL) to patients with advanced cancer. Although 
able to kill tumour targets in vitro, LAK cells did not prove useful for the 
treatment of patients with metastatic melanoma and renal cancer. A randomised 
trial, in which IL-2 was administered alone or with LAK cells, failed to show a 
difference in response rate or survival. In contrast, the treatment of 86 
patients with metastatic melanoma using TIL plus IL-2 resulted in a 34% 
objective response rate, which included patients who had previously failed 
treatment with high-dose IL-2 alone. The focus on cellular immune responses, 
combined with rapid biotechnological advances, resulted in the identification of 
tumour specific antigens, such as MART-1 and gp100, that could be recognised by 
autologous TIL. This provided fundamental evidence of the existence of 
melanoma-associated antigens that were recognised in vivo by effector cells of 
the immune system. In vitro studies demonstrated immunodominant epitopes from 
MART-1 and gp100 that could induce in vitro-specific cytotoxic T lymphocyte 
reactivity. To enhance in vitro immunogenicity, single amino acid substitutions 
were made to identify peptides with higher affinity for HLA-A*0201. Modified 
peptides from gp100 were compared with the parental peptide for increased 
immunogenicity based on their ability to induce anti-tumour lymphocytes in 
vitro. From these studies, a candidate peptide was identified (G9-209-2M) which 
had increased immunogenic reactivity in vitro. Clinical trials demonstrated that 
the modified G9-209-2M peptide was more effective. Unfortunately, objective 
tumour regression was still low. However, when high-dose IL-2 was combined with 
G9-209-2M objective clinical responses increased to 42%. Efforts to find better 
ways to immunise against self antigens are ongoing and involve further peptide 
immunisations, as well as recombinant viral vectors, adjuvant cytokine therapy 
and cellular adjuvants such as dendritic cells.