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Cancer Immunotherapy with Interleukin 12 and Granulocyte-Macrophage Colony-stimulating Factor-encapsulated Microspheres

Coinduction of Innate and Adaptive Antitumor Immunity and Cure of Disseminated Disease¹

Department of Surgery, Roswell Park Cancer Institute, Buffalo, New York 14263 [H. C. H., M. S. S.]; Department of Microbiology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214 [T. F. C., R. B. B., N. K. E.]; and Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912 [Y. S. J., E. M.]

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- 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.

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