Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy

Hum Gene Ther. 2016 Feb;27(2):184-92. doi: 10.1089/hum.2015.151.

Abstract

The vast majority (85%) of pancreatic ductal adenocarcinomas (PDACs) are discovered at too of a late stage to allow curative surgery. In addition, PDAC is highly resistant to conventional methods of chemotherapy and radiotherapy, which only offer a marginal clinical benefit. Consequently, the prognosis of this cancer is devastating, with a 5-year survival rate of less than 5%. In this dismal context, we recently demonstrated that PDAC gene therapy using nonviral vectors is safe and feasible, with early signs of efficacy in selected patients. Our next step is to transfer to the clinic HIV-1-based lentiviral vectors (LVs) that outshine other therapeutic vectors to treat experimental models of PDAC. However, a primary safety issue presented by LVs that may delay their use in patients is the risk of oncogenesis after vector integration in the host's cell DNA. Thus, we developed a novel anticancerous approach based on integrase-defective lentiviral vectors (IDLVs) and demonstrated that IDLVs can be successfully engineered to transiently deliver therapeutic genes to inhibit pancreatic cancer cells proliferation. This work stems for the use of therapeutic IDLVs for the management of PDAC, in forthcoming early phase gene therapy clinical trial for this disease with no cure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Genes, Reporter
  • Genetic Therapy / methods
  • Genetic Vectors / chemistry*
  • Genetic Vectors / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HIV-1 / genetics
  • HIV-1 / metabolism
  • Humans
  • Injections, Subcutaneous
  • Integrases / genetics*
  • Integrases / metabolism
  • Lentivirus / genetics*
  • Lentivirus / metabolism
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Transplantation, Heterologous
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Viral Proteins
  • Deoxycytidine
  • Green Fluorescent Proteins
  • gemcitabine
  • Integrases

Supplementary concepts

  • Pancreatic Carcinoma