Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.
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.
Division of Surgical Oncology, University of Michigan, Ann Arbor, MI, USA. msabel@umich.edu
Michael S
MS
Sabel
Gang
G
Su
Kent A
KA
Griffith
Alfred E
AE
Chang
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004337:Drug Carriers; D004339:Drug Compounding; D004357:Drug Synergism; D005260:Female; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000008:administration & dosage; D020382:Interleukin-18 / Q000008:administration & dosage; D019344:Lactic Acid / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D011091:Polyesters; D011108:Polymers / Q000737:chemistry*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D004337:Drug Carriers; D020382:Interleukin-18; D011091:Polyesters; D011108:Polymers; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019344:Lactic Acid; C033616:poly(lactide)