Generation of a tumor-specific systemic response after intratumoral injection of IL-12 and IL-18-loaded polylactic acid microspheres

J Immunother. Nov-Dec 2007;30(8):808-16. doi: 10.1097/CJI.0b013e318156e6a7.

Abstract

We evaluated the impact and mechanism of interleukin (IL)-18 alone or in combination with IL-12 or tumor necrosis factor-alpha when delivered intratumorally via polylactic acid microspheres (PLAMs). C57BL6 mice with established B16 melanomas underwent a single intratumoral injection of IL-12, tumor necrosis factor-alpha, or IL-18 PLAM, alone or in combination. Tumor draining lymph nodes and splenocytes were assessed for specific antitumor response by FACS analysis and IFN-gamma release assay and enzyme-linked immunosorbent spot. Mice with established pulmonary metastases were killed for enumeration of pulmonary metastatic nodules after treatment of the primary tumor. Intratumoral treatment with IL-12 in combination with IL-18 led to significant tumor suppression compared with either cytokine alone. FACS analysis revealed the combination of IL-12 and IL-18 resulted in an increase in the percentage of CD3+ cells within the tumor draining lymph node, attributable to increases in both CD4+ and CD8+ T cells. Both IFN-gamma release assay and enzyme-linked immunosorbent spot demonstrated a significant and substantial increase in tumor-specific response with the combination. Treatment of the primary tumor with IL-12 and IL-18 PLAM led to a significant decrease in pulmonary metastases and improvement in survival compared with either cytokine alone. The systemic effects were abrogated after depletion of CD8+ or natural killer cells, but not CD4+ cells. IL-12 and IL-18, when released intratumorally in a sustained fashion as can be accomplished through the use of PLAM, demonstrate both local effects on tumor growth and the generation of a tumor-specific response capable of eradicating distant disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Coculture Techniques
  • Drug Therapy, Combination
  • Female
  • Injections, Intralesional
  • Interferon-gamma / metabolism
  • Interleukin-12 / administration & dosage
  • Interleukin-12 / therapeutic use*
  • Interleukin-18 / administration & dosage
  • Interleukin-18 / therapeutic use*
  • Killer Cells, Natural / immunology
  • Lactic Acid / chemistry*
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Nanocapsules / chemistry*
  • Polyesters
  • Polymers / chemistry*
  • Spleen / cytology
  • Spleen / immunology
  • Survival Analysis
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / therapeutic use

Substances

  • Interleukin-18
  • Nanocapsules
  • Polyesters
  • Polymers
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Lactic Acid
  • poly(lactide)
  • Interferon-gamma