Generation of a tumor-specific systemic response after intratumoral injection of IL-12 and IL-18-loaded polylactic acid microspheres.
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.
Division of Surgical Oncology, University of Michigan, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0932, USA. msabel@umich.edu
Michael S
MS
Sabel
Alisha
A
Arora
Gang
G
Su
Kent A
KA
Griffith
Edith
E
Mathiowitz
Joshua J
JJ
Reineke
Alfred E
AE
Chang
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004359:Drug Therapy, Combination; D005260:Female; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D019344:Lactic Acid / Q000737:chemistry*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000737:chemistry*; D011091:Polyesters; D011108:Polymers / Q000737:chemistry*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use
D020382:Interleukin-18; D053769:Nanocapsules; D011091:Polyesters; D011108:Polymers; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019344:Lactic Acid; C033616:poly(lactide); D007371:Interferon-gamma