Antitumor and antimetastatic activity of interleukin 12 against murine tumors

By M. Brunda, Leopoldo L. Luistro, R. Warrier, R. Wright, B. R. Hubbard, Molly Murphy, S. Wolf, M. Gately. 1993

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.

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Citations in the corpus

• The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-γ Expression1 (2000, background): “In vivo, IL-12 increases inflammatory responses and anti-tumor activity (2).”
• The Antibody-Based Delivery of Interleukin-12 to the Tumor Neovasculature Eradicates Murine Models of Cancer in Combination with Paclitaxel (2012, background): “Brunda and colleagues reported impressive therapeutic results in different models of cancer following the intraperitoneal administration of the cytokine, although no cures were achieved (17).”
• Interleukin 12: still a promising candidate for tumor immunotherapy? (2014, background): “This cytokine has been successfully applied in dozens of experimental models in mice involving both solid tumors and hematologic malignancies including poorly immunogenic tumors [56–60].”
• Differential Tumor Surveillance by Natural Killer (Nk) and Nkt Cells (2000, unknown): “Data using bg/bg beige (44) and Ja2812/2 (9) mice supports this hypothesis.”