Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.

Abstract

Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.

• Authors: Michael S Sabel, Gang Su, Kent A Griffith, Alfred E Chang
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 122 Issue 2 Pg. 325-36 (Jul 2010) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 19802695 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Drug Carriers
• Interleukin-18
• Polyesters
• Polymers
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• Interleukin-12
• Lactic Acid
• poly(lactide)

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (chemistry, pharmacology)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Carcinoma (drug therapy, immunology, pathology)
• Cells, Cultured
• Chemistry, Pharmaceutical
• Dendritic Cells (drug effects, immunology)
• Drug Carriers
• Drug Compounding
• Drug Synergism
• Female
• Injections, Intralesional
• Interleukin-12 (administration & dosage)
• Interleukin-18 (administration & dosage)
• Lactic Acid (chemistry)
• Lung Neoplasms (drug therapy, immunology, pathology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Mammary Neoplasms, Experimental (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Microspheres
• Polyesters
• Polymers (chemistry)
• Recombinant Proteins (administration & dosage)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• Time Factors
• Tumor Necrosis Factor-alpha (administration & dosage)