Inhibition of a vascular ocular tumor growth by IL-12 gene transfer

Abstract

Ocular tumors such as retinoblastoma and uveal melanoma have devastating effects on vision. Patients with uveal melanoma also have low 5-year survival rates, thus new therapeutic modalities are necessary. As both retinoblastoma and uveal melanoma are highly vascular, we tested application of a gene transduction approach with a potent TH1 cytokine also endowed with strong anti-angiogenic activity, Interleukin-12 (IL-12). Gene transfer into murine 99E1 uveal melanoma-like cells, while having no effects on growth in vitro, essentially blocked subcutaneous tumor growth in vivo without evident signs of toxicity. Orthotopic intraocular injection resulted in invasive tumors that destroyed ocular architecture by the control cells while the IL-12 transduced cells rarely formed tumors. Histological analysis revealed highly invasive and angiogenic tumor growth in the controls and poorly vascularized tumors in the presence of IL-12. The tumor repression effect could be reproduced by a systemic anti-angiogenic effect, where controlateral injection of IL-12 expressing cells strongly repressed growth in tumors formed by parental 99E1 cells. This was associated with significantly lowered tumor vessel densities, a trend toward lower VEGF levels in the lesion, and significantly decreased NK cells in the parental tumors exposed to systemic IL-12. Taken together, our data suggest that IL-12 gene transfer can provide anti-angiogenic effects without toxicity and may be particularly suited for therapy of vascularized ocular tumors.

Rapid release of cytoplasmic IL‐15 from tumor‐associated macrophages is an initial and critical event in IL‐12‐initiated tumor regression

“…Given the role of functionally polarized Mϕ in tumor metastasis 6–10, it is possible that modulation of Mϕ function by IL‐12 reduced the rate of tumor metastasis, thus reducing seeding of the lungs from animals treated with IL‐12 plus anti‐IL‐15 antibody but not reducing the growth of, nor destroying, metastatic lesions existing at the time of treatment with IL‐12 plus anti‐IL‐15. Indeed, IL‐12 has been reported to interfere with tumor angiogenesis 37–39, 51, which is known to be highly dependent on tumor‐associated Mϕ function 8. We observed that IL‐12 reduced the expression of VEGF, MIF, and TGF‐β, all of which contribute to angiogenesis and/or metastasis (Fig.…”

“…The change in functional phenotype included a reduction in tumor‐supportive and immunosuppressive activities (MIF, TGF‐β, CCL2, and IL‐10 expression) and an increase in inflammatory, pro‐immunogenic activities (TNF‐α, IL‐6, IL‐15, and IL‐18 expression). IL‐12 has also been reported to inhibit angiogenic activity within the tumor, in part by reducing the activity of angiogenic factors such as VEGF 37–39. To determine if treatment with IL‐12 microspheres reduced VEGF secretion by Mϕ present in the primary tumor mass, Mϕ were purified from the primary tumor mass of mice treated with placebo microspheres or IL‐12 microspheres 24 h previously and cultured overnight without stimulus.…”

Peritumoral administration of granulocyte colony-stimulating factor induces an apoptotic response on a murine mammary adenocarcinoma

“…Furthermore, cytokine array assays showed that G-CSF treatment induced higher levels of IL-12, a cytokine previously evaluated as an effective antitumor agent that enhances the cytotoxic activity of immune cells. 35,36 An increment in the amount of IL-13 was also evident. Although IL-13 has been formerly related to allergic inflammation and fibrosis formation, it has been recently reported that IL-13 promotes the apoptosis of endothelial cells and RANTES, SCF, sTNFRI, TNFα, thrombopoietin, VEGF.…”