Immunotherapy for murine K1735 melanoma: combinatorial use of recombinant adenovirus expressing CD40L and other immunomodulators

Cancer Gene Ther. 2002 Jul;9(7):597-605. doi: 10.1038/sj.cgt.7700475.

Abstract

We have constructed and tested five recombinant adenoviruses (Ads) that express a variety of immunomodulators, including CD40 ligand (CD40L), a potent costimulator of several components of the immune system. We demonstrate that CD40L expressed from Ad in K1735 mouse melanoma cells leads to a strong reduction in tumorigenicity and to efficient protective immunity in a vaccination setting. Subsequently, using a therapeutic approach, we found that local, intratumoral coinjection of CD40L- and IL-2-expressing Ads was superior to any other agents tested and resulted in an at least 1.9-fold increase in mean survival time, in contrast to systemic application of recombinant CD40L or GM-CSF proteins, which had no significant effects. When using vaccination as a therapeutic approach, the combinations of CD40L plus IL-2 or GM-CSF plus IL-2 from Ad gave rise to an extended (2.8-fold) increase in mean survival time. A detailed analysis of immune cells present within regressing tumors indicated that mainly CD4(+) and CD8(+) T cells, and to a lesser extent dendritic cells, infiltrated the tumor mass, but not NK cells, macrophages, or granulocytes. These results propose that a combination of CD40L plus IL-2 has an improved efficacy over the use of single agents when applied for direct in situ therapy or vaccination therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • CD40 Ligand / genetics*
  • Disease-Free Survival
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Genetic Therapy / methods*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Granulocytes / metabolism
  • Immunohistochemistry
  • Immunotherapy / methods*
  • Interleukin-2 / metabolism
  • Killer Cells, Natural / metabolism
  • Macrophages / metabolism
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Transplantation
  • Time Factors
  • Tumor Cells, Cultured
  • Vaccines, DNA

Substances

  • Interleukin-2
  • Vaccines, DNA
  • CD40 Ligand
  • Granulocyte-Macrophage Colony-Stimulating Factor