Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12

Cancer Gene Ther. Jan-Feb 1999;6(1):45-53. doi: 10.1038/sj.cgt.7700013.

Abstract

Direct intratumoral (i.t.) injection of adenoviruses (Ads) expressing specific immunostimulatory cytokines represents an attractive strategy for the clinical implementation of cytokine gene therapy of cancer. Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells and promotes a T helper 1-like immune response. We have constructed an Ad vector (AdCMV-mIL-12) containing both chains of the murine IL-12 (mIL-12) gene linked by an internal ribosomal entry site sequence under the transcriptional control of the cytomegalovirus immediate-early gene promoter, which is able to mediate the transient expression of very high levels of biologically active mIL-12 both in vitro and in vivo. An i.t. injection of 4x10(8) plaque-forming units of AdCMV-mIL-12 resulted in a complete regression of day 7 established subcutaneous MC38 murine adenocarcinomas and MCA205 murine fibrosarcomas. Treated animals rejected a subsequent rechallenge with MC38 and MCA205, respectively, demonstrating the induction of long-lasting antitumor immunity. Specific antitumor cytotoxic T lymphocyte reactivity was detected in splenocytes harvested from treated animals. A significant increase in the numbers of both CD4+ and CD8+ T cells in the AdCMV-mIL-12-infected tumors was observed. Ad-mediated IL-12 gene therapy was also associated with measurable serum levels of mIL-12 and profound changes in the composition of splenic lymphocytes. Taken together, these results demonstrate the feasibility and efficacy of delivering IL-12 directly i.t. using a recombinant adenoviral vector.

Publication types

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

MeSH terms

  • Adenocarcinoma / immunology*
  • Adenocarcinoma / therapy
  • Adenoviridae / genetics
  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibrosarcoma / immunology*
  • Fibrosarcoma / therapy
  • Genetic Vectors
  • Immunotherapy*
  • Injections, Intralesional
  • Interferon-gamma / blood
  • Interferon-gamma / pharmacology
  • Interleukin-12 / genetics*
  • Interleukin-12 / pharmacology
  • Interleukin-12 / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Recombinant Proteins
  • Interleukin-12
  • Interferon-gamma