DNA vaccines employing intracellular targeting strategies and a strategy to prolong dendritic cell life generate a higher number of CD8+ memory T cells and better long-term antitumor effects compared with a DNA prime-vaccinia boost regimen

Hum Gene Ther. 2005 Jan;16(1):26-34. doi: 10.1089/hum.2005.16.26.

Abstract

We have previously shown that intradermal coadministration of DNA encoding Bcl-x(L), an antiapoptotic protein, with DNA encoding E7 antigen linked to the sorting signal of the lysosome-associated membrane protein type 1 (Sig/E7/LAMP-1) prolongs dendritic cell life and enhances antigen presentation through the MHC class I and II pathways. In the current study, we compared this approach with a conventional DNA prime-vaccinia boost protocol on the basis of their ability to generate antigen-specific CD8(+) memory T cells and longterm antitumor effects against an E7-expressing tumor. Mice primed and boosted with Sig/E7/LAMP-1 DNA mixed with Bcl-x(L) DNA generated significantly higher numbers of E7-specific CD8(+) memory T cells and a better long-term protective antitumor effect compared with mice primed with Sig/E7/LAMP-1 DNA and boosted with Sig/E7/LAMP-1 vaccinia (Vac-Sig/E7/LAMP-1). Furthermore, coadministration of Sig/E7 /LAMP-1 DNA mixed with Bcl-x(L) DNA also generated higher avidity E7-specific CD8(+) T cells than did vaccination with Sig/E7/LAMP-1 DNA followed by a Vac-Sig/E7/LAMP-1 booster. Our results indicate that coadministration of a DNA vaccine employing intracellular targeting strategies and a DNA encoding antiapoptotic proteins may potentially generate a higher number of memory CD8(+) T cells and better long-term protective antitumor effects compared with the conventional DNA prime-vaccinia boost regimen.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity, Immunologic / genetics
  • Dendritic Cells / immunology*
  • Drug Delivery Systems
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Targeting*
  • Interferon-gamma / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / therapy*
  • Lysosome-Associated Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Proteins, Viral / administration & dosage
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / immunology
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Th1 Cells / immunology
  • Th1 Cells / virology
  • Vaccines, DNA / administration & dosage*
  • Vaccinia virus / genetics
  • bcl-X Protein

Substances

  • Antigens, CD
  • Bcl2l1 protein, mouse
  • Epitopes, T-Lymphocyte
  • Lysosome-Associated Membrane Glycoproteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Vaccines, DNA
  • bcl-X Protein
  • oncogene protein E7, Human papillomavirus type 16
  • Interferon-gamma