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Intratumoral vaccination of adenoviruses expressing fusion protein RM4/tumor necrosis factor (TNF)-alpha induces significant tumor regression.

Abstract
Recombinant adenovirus (AdV) vectors are highly efficient at in vitro and in vivo gene delivery. VKCK is a murine myeloma cell line expressing the light chain of the fusion protein RM4/tumor necrosis factor (TNF)-alpha. The in vitro transfection of VKCK cells with the AdV AdV5LacZ, which contains the marker gene beta-galactosidase, can reach a maximal 75% at a multiplicity of infection of 1000. Intratumoral injections of AdV5LacZ (2 x 10(9) plaque-forming units) resulted in substantial gene transfer in nearly 50% of VKCK tumors. The AdV pLpA/M4-TNF-alpha, which contains a fused gene M4-TNF-alpha that codes for the heavy chain of fusion protein RM4/TNF-alpha, was constructed. After the in vitro transfection of pLpA/M4-TNF-alpha at a multiplicity of infection of 1000, transfected VKCK cells showed significant secretion of RM4/TNF-alpha (36 ng/mL/10(6) cells) containing the functional TNF-alpha moiety in tissue culture. The secretion peaks at day 3 and is diminished at day 6 following the viral infection. These transfected VKCK cells also became more immunogenic with enhanced expression of major histocompatibility complex class I antigen. Intratumoral injections of 2 x 10(9) plaque-forming units of pLpA/M4-TNF-alpha virus with a repeated booster resulted in significant VKCK tumor regression in immune-competent mice, but not in athymic nude mice with a mean tumor weight of 0.07 g that were compared with 1.58 g and 1.70 g for tumors injected with AdV5LacZ and phosphate-buffered saline, respectively (P < .01). The tumor regression also results in protective immunity against a second challenge with parental tumor cells, which is mainly mediated by VKCK tumor-specific CD8+ T cells. These results indicate that AdV-mediated cytokine gene therapy may be a useful approach in the clinical management of solid human tumors.
AuthorsP Wright, C Zheng, T Moyana, J Xiang
JournalCancer gene therapy (Cancer Gene Ther) 1998 Nov-Dec Vol. 5 Issue 6 Pg. 371-9 ISSN: 0929-1903 [Print] UNITED STATES
PMID9917092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cancer Vaccines
  • Immunoglobulin Fab Fragments
  • RM4-TNF protein, recombinant
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • Vaccines, DNA
Topics
  • Adenoviridae (genetics, metabolism)
  • Animals
  • CD8-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (therapeutic use)
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Genes, Reporter
  • Humans
  • Immunoglobulin Fab Fragments (genetics)
  • Kinetics
  • Lac Operon
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multiple Myeloma (immunology, therapy)
  • Neoplasm Transplantation
  • Recombinant Fusion Proteins (genetics, metabolism)
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha (genetics)
  • Vaccines, DNA (therapeutic use)

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