Immunotherapy of established tumors in mice by intratumoral injection of interleukin-2 plasmid DNA: induction of CD8+ T-cell immunity

Cancer Gene Ther. Sep-Oct 1998;5(5):321-30.

Abstract

Intratumoral (i.t.) injection of a plasmid DNA vector encoding the murine interleukin-2 (IL-2) gene was used to treat established renal cell carcinoma (Renca) tumors in BALB/c mice. Tumor regression was observed in 60-90% of mice that were injected i.t. for 4 days with IL-2 plasmid DNA complexed with the cationic lipid DMRIE/DOPE ((+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propa naminium bromide/dioleoylphosphatidylethanolamine). The mice remained tumor-free until the conclusion of the study, which was 4 months after tumor challenge. In a rechallenge experiment, mice that were rendered tumor-free for 6 months by IL-2 plasmid DNA treatment rejected a subsequent challenge of Renca cells but could not reject a challenge with the unrelated, syngeneic CT-26 tumor. Spleen cells from cured mice contained Renca-specific cytotoxic T lymphocytes, and adoptive transfer of mixed lymphocyte cultures into naive mice at 2 days after challenge with Renca cells prevented tumor growth. In vivo depletion of T-cell subsets at the time of i.t. injection with IL-2 plasmid DNA demonstrated that CD8+ T cells, but not CD4+ T cells, were the primary effectors of the antitumor response.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenicity Tests
  • Carcinoma, Renal Cell / immunology*
  • Carcinoma, Renal Cell / therapy*
  • Dose-Response Relationship, Drug
  • Drug Carriers / pharmacology
  • Immunotherapy / methods*
  • Injections, Intralesional
  • Interleukin-2 / genetics*
  • Interleukin-2 / pharmacology
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / therapy
  • Lipids / chemistry
  • Lipids / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / pharmacology
  • Plasmids / genetics
  • Plasmids / pharmacology*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology

Substances

  • Drug Carriers
  • Interleukin-2
  • Lipids
  • Phosphatidylethanolamines
  • Quaternary Ammonium Compounds
  • (3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium
  • dioleoyl phosphatidylethanolamine