T-cell-directed cancer vaccines: the melanoma model

Significant advances in the understanding of the molecular basis for tumour /host interactions in humans have occurred in the last decade through study ing patients with metastatic melanoma. This disease is characterised by its tendency to be modulated by immunologic factors. Furthermore, immunologic manipulation of the host with various systemic agents, in particular IL-2, frequently affects this natural phenomenon and can lead to complete rejecti on of cancer. By studying the cellular immunology occurring in patients und ergoing immunotherapy, several tumour antigens (TA) and their epitopes reco gnised by human leukocyte antigen (HLA) class I-restricted cytotoxic T-lymp hocytes (CTL) have been identified. Most of these TA are non-mutated molecu les expressed by the majority of melanoma in vivo and most melanoma cell li nes. In addition, unique minimal epitopic sequences play an immunodominant role in the context of specific HLA class I alleles. Since melanoma lesions from different patients often share expression of the same TA, and a minim al peptide sequence from a TA can cause immunologic changes in multiple pat ients, interest has grown in the development of TA-specific vaccines suitab le for broad patient populations. Repeated in vitro stimulation of peripher al blood mononuclear cells (PBMC) with TA-derived epitopes can induce a hig h frequency of TA-reactive T-cells in melanoma patients. The same epitopes can also enhance TA-specific T-cell reactivity in vivo when administered su bcutaneously in combination with Incomplete Freund's Adjuvant (IFA). Epitop e-based vaccinations, however, have not shown strong clinical efficacy unle ss combined with IL-2 administration. Attempts to increase the efficacy of these vaccines have combined specialised antigen-presenting cells or the ad ministration of whole TA through DNA- or RNA-based vaccines with the intent ion of increasing antigen presentation and processing. Save for scattered r eports, however, the success of these approaches has been limited and T-cel l-directed vaccination against cancer remains at a paradoxical standstill w hereby anticancer immunisation can be induced but it is not sufficient, in most cases, to induce tumour regression. Using melanoma as the standard mod el for immunotherapy, we will review various methods of T-cell-directed vac cination, the monitoring and analysis of the resulting immune response, and several clinical trials in which cancer vaccines have successfully induced immunisation.