A tumor-targeted and conditionally replicating oncolytic adenovirus vector expressing TRAIL for treatment of liver metastases

Mol Ther. 2004 Apr;9(4):496-509. doi: 10.1016/j.ymthe.2003.12.008.

Abstract

We have constructed a new capsid-modified adenovirus (Ad) vector that specifically replicates in tumor cells and expresses TNF-related apoptosis-inducing ligand (TRAIL). The Ad capsid contains short-shafted fibers derived from Ad serotype 35, which allow for efficient infection of malignant tumor cells, and largely avoids innate toxicity after intravenous application. Replication-dependent homologous recombination in Ad genomes was used to achieve tumor-specific expression of Ad E1a (to mediate viral replication) and TRAIL (to mediate apoptosis and enhance release of progeny virus from infected cells). We demonstrated that our oncolytic vector (Ad5/35.IR-E1A/TRAIL) induced apoptosis in human tumor cell lines derived from colorectal, lung, prostate, and liver cancer. Both in vitro and in vivo tumor models showed efficient intratumoral spread of this vector. In a model for metastatic colon cancer, tail vein infusion of Ad5/35.IR-E1A/TRAIL resulted in elimination of preestablished liver metastases. Intravenous injection of this vector caused a transient elevation of serum glutamic pyruvic transaminase in tumor-bearing mice, which we attributed to factors released from apoptotic tumor cells. Liver histology analyzed at day 14 after virus injection did not show signs of hepatocellular damage. This new oncolytic vector represents a potentially efficient means for gene therapy of metastatic cancer.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Adenovirus E1A Proteins / metabolism
  • Alanine Transaminase / blood
  • Animals
  • Antigens, CD / genetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Capsid
  • Caspase 3
  • Caspases / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Colonic Neoplasms / pathology
  • Female
  • Gene Transfer Techniques*
  • Genetic Vectors
  • Genome, Viral
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / diagnosis*
  • Liver Neoplasms / secondary*
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Plasmids / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism
  • Uterine Cervical Neoplasms / metabolism

Substances

  • Adenovirus E1A Proteins
  • Antigens, CD
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • CD46 protein, human
  • Mcp protein, mouse
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Alanine Transaminase
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases