Genetically modified tumour vaccines--where we are today

Tumour vaccines are based on weakly immunogenic specific tumour antigens admixed with adjutants in order to elicit, restore or augment antitumour immune responses against residual or metastatic tumour cells. Cellular cytotoxicity is considered to play a major role in eliminating tumour cells. Activation of cellular toxicity requires at least three synergistic signals: presentation of specific tumour antigen, constimulatory signal (B7 molecules) and propagation signal (cytokines). Recently several HLA-restricted specific tumour antigens recognized by cytotoxic T-cells have been characterized. Antibody defined antigens, heat shock proteins and viral antigens are also discussed. First generation vaccines made of whole cancer cells or tumour-cell lysates together with non-specific adjutants produced about 20% of clinical responses and are currently tested in prospective clinical trials. Novel second generation of tumour vaccines employ genetically modified tumour cells, antigen presenting cells (dendritic cells) or recombinant tumour antigens. Tumour cells are modified with genes encoding molecules providing signals for cytotoxic T-cells required for recognition and killing of cancer cells such as B7 constimulatory molecules, HLA proteins and genes of different cytokines. Dendritic cells are modified with genes of specific tumour antigens in order to activate both helper and cytotoxic T-cells. Novel vaccines produce specific immune responses and objective clinical responses with minimal toxicity in phase I/II trials. Advances in gene transfer technology, tumour immunology and better methods of monitoring specific antitumour immune responses allow the hope that tumour vaccines will be introduced into the clinic, at least in some malignancies resistant to systemic therapy so far such as melanoma and renal cell carcinoma.