Cancer vaccines: an update.

This review summarizes the most recent findings and the future directions in designing cancer vaccines. The newest tumor-associated antigens and the most promising approaches to cancer vaccine development are discussed. We categorized them as follows: peptide vaccines, recombinant viral vaccines, DNA vaccines, dendritic cell-based immunotherapy, and the use of heat shock proteins and adjuvants. We focus on their advantages and disadvantages in addition to clinical potential.

Synthetic insertion signal sequences enhance MHC class I presentation of a peptide from the melanoma antigen MART-1.

Cytotoxic T lymphocytes (CTL) recognize minimal peptides of eight to ten residues which are the products of intracellularly processed proteins and are presented at the cell surface by MHC class I molecules. An important step in this process is the translocation of processed proteins from the cytosol across the endoplasmic reticulum membrane mediated by transporter associated with antigen processing (TAP) proteins, or as an alternative, by endoplasmic reticulum insertion signal sequences. We report here that the addition of synthetic signal sequences at the N terminus, but not at the C terminus, of an epitope from the human melanoma antigen MART-1 greatly enhances its presentation in both TAP-deficient and TAP-expressing cells. A newly designed peptide construct, composed of the epitope replacing the hydrophobic part of a natural signal sequence, was also very effective. Interestingly, an artificial signal sequence containing the same epitope was the most efficient construct for enhancing its presentation. These peptide constructs facilitated epitope presentation when loaded into the cytosol of TAP-deficient T2 cells, TAP-expressing melanoma cells and human dendritic cells. These findings may be of practical significance for the development of synthetic anti-cancer vaccines and in vitro immunization of CTL for adoptive immunotherapy.

Cancer vaccines: novel approaches and new promise.

Cancer vaccines are a promising tool in the hands of the clinical oncologist. We have summarized the most recent findings and achievements in this exciting field. Tumor-associated antigens, as a basis for the new cancer vaccines, are reviewed. We emphasize novel approaches for the design of safe and more effective vaccines for cancer. We also discuss the possible clinical applications and the future prospects for vaccine development.

New trends in the development of cancer vaccines.

Recent advances in understanding of the molecular mechanisms of antigen processing and presentation, and the identification of tumor-associated antigens in melanoma and other cancers, have stimulated the development of a new generation cancer vaccines. This review summarizes the most recent approaches for the design of safe and more effective vaccines for cancer. Peptide-based vaccines are safe and can be synthesized with high purity and reproducibility. Recombinant viruses encoding tumor-associated antigens allow efficient delivery and precise control over the form and the quantity of the delivered antigens. DNA-based vaccines induce long-lasting immune responses and are considered very safe. Antigen-loaded dendritic cells, and the use of newly developed adjuvants are also very promising new approaches. In this review, we also discuss the possible clinical applications and future directions for vaccine development.

Insertion signal sequence fused to minimal peptides elicits specific CD8+ T-cell responses and prolongs survival of thymoma-bearing mice.

CD8+ T-lymphocytes (TCD8+) recognize minimal peptides of 8-10 residues which are the products of intracellularly processed proteins and are presented at the cell surface by major histocompatibility complex class I molecules. An important step in this process is the translocation of processed proteins from the cytosol across the endoplasmic reticulum membrane, mediated by transporter associated with antigen-processing proteins or alternatively by endoplasmic reticulum-insertion signal sequences located at the NH2-terminus of the precursor molecules. We report here that the addition of an endoplasmic reticulum-insertion signal sequence at the NH2-terminus of TCD8+ epitopes from chicken ovalbumin (amino acids 257-264) or a naturally occurring tumor antigen expressed by the murine mastocytoma P815 (P1A amino acids 35-43) significantly enhanced the priming of specific TCD8+ in vivo. The signal sequence did not enhance peptide immunogenicity by merely increasing the hydrophobicity of the peptide, since ovalbumin amino acids 257-264 peptide with the signal sequence at its COOH-terminus did not demonstrate enhanced efficacy. The signal sequence did not act as a helper epitope, since TCD8+ responses were not diminished in class II-deficient transgenic mice or in mice depleted of CD4+ T-cells in vivo. Importantly, a single immunization with the fusion peptide significantly prolonged survival of mice challenged with E.G7OVA, a thymoma transfected with the complementary DNA of chicken ovalbumin.

Enhancing the recognition of tumour associated antigens.

Activated CD8+ T cells (TCD8+) can directly recognize malignant cells because processed fragments of tumour associated antigens (TAA), 8-10 amino acids in length and complexed with MHC class I molecules, are displayed on tumour cell surfaces. Tumour cells have been genetically modified in a variety of ways in efforts to enhance the immune recognition of TAA. An alternative strategy is the expression of TAA in recombinant or synthetic form. This has been made possible by the recent cloning of TAA recognized by TCD8+. In this communication we review recent work in our own laboratory on the expression of TAA as synthetic peptide, by "naked" plasmid DNA injected intramuscularly or transdermally, and by recombinant viruses including vaccinia (rVV), fowlpox (rFV) and adenovirus (rAd). The expression of TAA in recombinant and synthetic forms allows increased control over the quantity, location, and kinetics of TAA presentation and can result in powerful, specific, anti-tumour immune responses.