Synthetic and natural non-live vectors: rationale for their clinical development in cancer vaccine protocols.

Different arguments suggest that cytotoxic CD8 T lymphocytes (CTL) play a key role in the protection against tumors and in the establishment of anti-tumor immunity. Unfortunately, administration of soluble proteins alone generally does not induce CD8+ T cells presumably because antigen derived peptides are not introduced into the major histocompatibility complex (MHC) class I antigen presentation pathway. Attenuated recombinant live vectors such as viruses or bacteria which have the ability to deliver antigen into the cytosol of cells have been shown to induce cytotoxic T cell response. However, there are safety concerns associated with these approaches especially in immunodeficient patients. Synthetic vectors such as heat shock proteins, virus like particles (VLP) and liposomes could deliver exogenous protein into the cytosol of cells associated with the induction of CTL and tumor immunity. We and other groups have successfully exploited the original intracellular traffic of toxins to use them as vectors for tumor antigens.

Development of non-live vectors and procedures (liposomes, pseudo-viral particles, toxin, beads, adjuvantsellipsis) as tools for cancer vaccines.

Recombinant virus encoding tumor antigens are the most used vectors in human clinical trials of cancer vaccines because of their ability to target exogenous antigen in the endogenous MHC class I pathway and to elicit CTL. However, their use requires different constraining procedures to avoid their spreading. The immunosuppression of cancer patients may also increase their intrinsic toxicity. Therefore, the development of non-live vectors may avoid these drawbacks. Different groups now clearly demonstrated that particulate antigens when they are phagocytosed could be targeted in the MHC class I pathway. They also induce CTL in mice which when immunized with these particulate antigens were protected against a challenge with tumors expressing this antigen. Other strategies using toxins or antigens fused or incorporated into various oil or lipid based chemical adjuvants have also succeeded in the induction of CTL response and in some cases have been shown to be efficient as cancer vaccine.