Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA

Schultz, Jan; Heinzerling, Lucie; Pavlovic, Jovan; Moelling, Karin

doi:10.1038/sj.cgt.7700273

Cited by 28 publications

(29 citation statements)

References 35 publications

(44 reference statements)

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“…injection of naked DNA of this plasmid resulted in longterm IL-12 production. 9,22 In agreement with these observations, i.m. injection 20 days prior to, or 20 days and 2 days prior to initiation of the angiogenesis assay, resulted in strong and significant angiogenesis inhibition (Figure 1b).…”

Section: Prevention Of Angiogenesis In Vivo By Il-12 Gene Therapysupporting

confidence: 85%

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

et al. 2004

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IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-g and angiostatic CXCR3 chemokine ligands. Naked DNA intramuscular injection of an expression vector plasmid producing IL-12 resulted in significant, well-tolerated elevation of serum IL-12 levels. Injection of the IL-12 plasmid at least 2 days, and up to 20 days, before subcutaneous injection of matrigel with angiogenic factors resulted in strong prevention of angiogenesis in both C57/bl and nude mice. A single injection of the IL-12 plasmid contemporarily with the matrigel or 2 days after resulted in partial, statistically not significant, inhibition. Control plasmid injection did not affect either angiogenesis or angiogenesis inhibition by IL-12 protein in vivo. Angiogenesis inhibition was observed in NK cell-depleted C57/bl and nude mice as well as in IFN-g À/À and CXCR3 À/À knockout mice, indicating that NK-and/or T-cell-initiated IFN-gchemokine cascades were not involved in the angiogenesis inhibition observed in vivo. Finally, IL-12 plasmid DNA gene transfer significantly prevented the growth and vascularization of highly angiogenic KS-Imm Kaposi's sarcoma and TS/ A murine mammary carcinoma tumors in nude and/or syngeneic mice. These data suggest that a preventive gene therapy approach using antiangiogenic cytokines can effectively inhibit tumor angiogenesis and KS, representing an example of angioimmunoprevention.

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Section: Prevention Of Angiogenesis In Vivo By Il-12 Gene Therapysupporting

confidence: 85%

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

et al. 2004

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“…It is unlikely that this mechanism was due to more viable tumor cells, which probably produced IL-12 by electroporation-mediated gene transfer, in immunosuppressed mice than in nonimmunosuppressed mice, because the pCAGGSmIL-12-transferred tumor volume, necrotic area, and number of tumor neovascularizations were comparable between nonimmunosuppressed mice and immunosuppressed mice. Considering a report suggesting that long-lasting IL-12 production by injection of IL-12-encoding plasmid DNA due to an autocrine or paracrine positive feedback mechanism whereby several cell population including NK cells are involved (52), long-lasting IL-12 production in our present study may also be due to the positive feedback mechanism by which the production of endogenous IL-12 is actually produced by host macrophages and dendritic cells. Moreover, Conboy et al (48) reported that FK506, a calcineurin inhibitor, acts in macrophages and fibroblasts to augment cytokines, IL-12 and TNF-␣, and this effect is paradoxical compared with that in naive T cells.…”

Section: Discussionsupporting

confidence: 51%

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

Harada¹,

Shimada²,

Okano

et al. 2004

The Journal of Immunology

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Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2k), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 × 106 MH134 cells (H-2k) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-γ, and IFN-γ-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2d) and tumors, B7-p815 (H-2d) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

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“…The use of IL-12 has generated significant interest in the field of tumor immunotherapy and on the basis of successful results obtained in preclinical models has been tested in Phase I and II clinical trials [13][14][15][16][17]. Several approaches have focused on the local release of IL-12 at the site of a tumor via methods including IL-12 transfected fibroblasts or DC [18] [19], in vivo transfection of tumor cells via viral vectors [20][21][22][23][24][25][26], or electroporation of plasmid DNA [4,[27][28][29][30]. Beyond the technical complexities and potential complications of these approaches, the clinical results have been disappointing and have dampened enthusiasm for intratumoral cytokine-based immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

“…RENCA is an immunogenic murine renal cell carcinoma of spontaneous origin in the Balb/c strain [4]. Cell lines were maintained in complete media consisting of RPMI 1640 supplemented with 10% heatactivated fetal bovine serum, 0.1 mM nonessential amino acids, 1 lM sodium pyruvate, 100 lg/ml streptomycin, 100 units/ml penicillin, 50 lg/ml gentamycin and 0.5 lg/ml fungizone, all from Life Technologies, Inc. (Grand Island, NY).…”

Section: Methodsmentioning

confidence: 99%

Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

Sabel

Griffith

et al. 2009

Breast Cancer Res Treat

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Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.

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Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA

Cited by 28 publications

References 35 publications

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

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