Development of cancer vaccines to activate cytotoxic T lymphocytes.

Cancer vaccines have been shown to stimulate cytotoxic T lymphocyte (CTL) responses in a variety of cancer patients. However, the response is often of low frequency and moderate avidity, and does not result in objective clinical responses. This is related to the target antigens, which are usually over-expressed self-antigens that elicit tolerogenic and regulatory immune responses, resulting in deletion or inactivation of high-avidity T cells. Although moderate-avidity T cells can be efficient killers, tumours are often poor targets as they express a variety of molecules to protect them from cell-mediated immunity. Adoptive transfer of large numbers of high-avidity T cells has been shown to induce regression of bulky disease, proving that immune responses can effectively eradicate tumours. New approaches that target activated dendritic cells in vivo, resulting in cross-presentation of CTL epitopes and release of cytokines that suppress regulatory T cells, have resulted in the production of T cells with sufficient avidity to kill tumour target cells. These approaches in combination with regimes, such as cytokine therapy, chemotherapy or radiotherapy, that modulate effector costimulatory expression on tumour targets may result in more effective second-generation cancer vaccines.