Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen.

Abstract

DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8(+) CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4(+) T cell responses. For induction of CD8(+) T cell responses, the FrC sequence has been engineered to remove potentially competitive MHC class I-binding epitopes and to improve presentation of tumor epitopes. The colon carcinoma CT26 expresses an endogenous retroviral gene product, gp70, containing a known H2-L(d)-restricted epitope (AH1). A DNA vaccine encoding gp70 alone was a poor inducer of CTL, and performance was not significantly improved by fusion of full-length FrC. However, use of a minimized domain of FrC, with the AH1 sequence fused to the 3' position, led to rapid induction of high levels of CTL. IFN-gamma-producing epitope-specific CTL were detectable ex vivo and these killed CT26 targets in vitro. The single epitope vaccine was more effective than GM-CSF-transfected CT26 tumor cells in inducing an AH1-specific CTL response and equally effective in providing protection against tumor challenge. Levels of AH1-specific CTL in vivo were increased following injection of tumor cells, and CTL expanded in vitro were able to kill CT26 cells in tumor bearers. Pre-existing immunity to tetanus toxoid had no effect on the induction of AH1-specific CTL. These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine.

• Authors: Jason Rice, Sarah Buchan, Freda K Stevenson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 169 Issue 7 Pg. 3908-13 (Oct 01 2002) ISSN: 0022-1767 [Print] United States
• PMID: 12244189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• Growth Inhibitors
• Recombinant Fusion Proteins
• Retroviridae Proteins, Oncogenic
• Tetanus Toxoid
• Vaccines, DNA
• Viral Envelope Proteins
• Interferon-gamma

Topics

• Animals
• Antigens, Neoplasm (administration & dosage, genetics, immunology)
• Cancer Vaccines (administration & dosage, chemical synthesis, genetics, immunology)
• Colonic Neoplasms (immunology, pathology, prevention & control)
• Cytotoxicity, Immunologic (genetics)
• Epitopes, T-Lymphocyte (administration & dosage, genetics, immunology)
• Growth Inhibitors (administration & dosage, chemical synthesis, genetics, immunology)
• Injections, Intramuscular
• Interferon-gamma (biosynthesis)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Recombinant Fusion Proteins (administration & dosage, chemical synthesis, genetics, immunology)
• Retroviridae Proteins, Oncogenic (administration & dosage, genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology, metabolism, transplantation)
• Tetanus Toxoid (administration & dosage, immunology)
• Vaccines, DNA (administration & dosage, chemical synthesis, genetics, immunology)
• Viral Envelope Proteins (administration & dosage, genetics, immunology)