Antitumor activity of interleukin 12 in preclinical models

Abstract

Interleukin 12 (IL-12) is a heterodimeric cytokine with a number of biological effects that are consistent with its potential role as an antitumor agent. The antimetastatic and antitumor activities of IL-12 have been demonstrated in a number of murine tumor models. Both the inhibition of established experimental pulmonary or hepatic metastases and a reduction in spontaneous metastases have been achieved by treatment with murine IL-12. Systemic treatment of mice bearing subcutaneous tumors with IL-12 results in tumor growth inhibition, prolongation of survival, and, in some models, tumor regression. The antitumor effect of IL-12 in these models is dose-dependent and can be initiated against well-established tumors. Mice cured of their tumor by IL-12 treatment are specifically immune to rechallenge with the same tumor. A series of experiments have demonstrated that both T-cells and interferon-gamma (IFN-gamma) induction are necessary for the optimal antitumor effects of IL-12. However, the antitumor efficacy of IL-12 has not been observed after exogenous administration of murine IFN-gamma, suggesting that additional factors may be important for the antitumor effects of IL-12. In several tumor models, IL-12 is more active or has a larger therapeutic window than either IL-2 or IFN-alpha, two cytokines with demonstrated antitumor activity against human malignancies. Combining IL-12 with other cytokines or chemotherapeutic drugs can improve antitumor effects.

Antitumoral effect of interleukin-12-secreting fibroblasts in a mouse model of ovarian cancer: Implications for the use of ovarian cancer biopsy-derived fibroblasts as a vehicle for regional gene therapy

“…First-strand cDNA was prepared using the first-strand cDNA synthesis kit (Life Technologies) according to the manufacturer's instructions; however random hexamer primers at 10 ng/ L (Amersham Pharmacia Biotech, Orsay, France) were substituted for oligo(dT) [12][13][14][15][16][17][18] .…”

“…Animal studies have revealed that IL-12 has powerful antitumoral, antimetastatic, and anti-angiogenic activities. [15][16][17][18] This potent antitumoral effect of IL-12 seems to depend upon stimulation of the immune system via direct activation of antitumoral natural killer cells and T lymphocytes, which express specific IL-12 receptors. 19,20 An important indirect mechanism of action is provided by the resulting secretion of interferon-␥ by these cells, which increases antigen presentation [21][22][23] and induces tertiary secretion of anti-angiogenic factors.…”

Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma

“…[23][24][25][26][27][28][29][30] IL-2 is the primary cytokine responsible for the activation and clonal expansion of CD8 ϩ cytotoxic T lymphocytes (CTLs), which are the primary effector cells that target tumors in an antigen-specific manner. 2 IL-12 functions to activate and clonally expand natural killer (NK) cells, which kill tumors in a major histocompatibility complex (MHC)-independent fashion.…”

Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12

“…IL-12 is a cytokine that mediates the T H 1-type immune response, stimulates natural killer (NK) cell activity, and has also been shown to have antiangiogenic properties [24][25][26] It has known antitumor properties in a variety of models. 25,27 We have previously demonstrated that a g 1 34.5-deleted HSV-1 expressing murine IL-12 (M002) prolonged survival of immunocompetent mice in an experimental intracranial murine model of neuroblastoma. 28 Recently, combinatorial cytokine therapy has been pursued in a wide array of cancer therapies.…”

“…IL-12 has been shown to have increased antitumor effects when used in combination with additional cytokines. 27 Because of its ability to stimulate chemotaxis of monocytes and numerous T-lymphocyte subsets, monocyte chemoattractant protein-1 (MCP-1), now called CCL2, is potentially a good candidate for increasing the antitumor effects of IL-12. CCL2 is a member of the C-C chemokine family and stimulates chemotaxis of monocytes, CD4 þ and CD8 þ , memory T lymphocytes and dendritic cells in vitro.…”