title: Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease.
abstract: Tumor cells, injected s.c., were maintained until spontaneous metastases to the lungs were established in all of the mice. Mice were then treated with a single dose of cytokine-encapsulated biodegradable microspheres injected directly into primary s.c. tumors to achieve a local and sustained release of interleukin 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of these cytokines to the tumor microenvironment. The s.c. tumors were surgically excised 6 days after microsphere injections, and the mice were monitored for recurrence of the primary tumor, survival, and progression of metastatic disease. Combined neoadjuvant treatment with IL-12 and GM-CSF microspheres was superior to all other treatments in reducing the recurrence of primary tumors, enhancing postoperative survival, and suppressing established metastatic disease. Long-term survival analysis demonstrated that intratumoral injection of IL-12 + GM-CSF-loaded microspheres resulted in the complete cure of disseminated disease in the majority of the animals. The addition of systemic low-dose IL-2 therapy to the treatment protocol resulted in the loss of the antitumor activity induced by IL-12 + GM-CSF treatment. In vivo lymphocyte subset depletions established that both T- and natural killer-cell subsets were required for the suppression of primary and metastatic tumors. Long-term, tumor-specific T-cell activity was demonstrated by immunohistochemical analysis of metastatic lesions, IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) assays and tumor challenge studies. These results establish that neoadjuvant in situ tumor immunotherapy with IL-12 + GM-CSF microspheres induces both innate and adaptive antitumor immune responses resulting in the eradication of disseminated disease.
authors.affiliation: Department of Surgery, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Hank C
authors.initials: HC
authors.lastname: Hill
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Conway
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.forename: Yong S
authors.initials: YS
authors.lastname: Jong
authors.forename: Edith
authors.initials: E
authors.lastname: Mathiowitz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Bankert
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D020360:Neoadjuvant Therapy; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor