title: Cancer immunotherapy: is there real progress at last?
abstract: 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.
authors.affiliation: Surgery Branch, Division of Clinical Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: U S
authors.initials: US
authors.lastname: Kammula
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola