Gene Gun-Mediated IL-12 Gene Therapy Induces Antitumor Effects in the Absence of Toxicity: A Direct Comparison With Systemic IL-12 Protein Therapy

Rakhmilevich, Alexander L.; Timmins, J G; Janssen, Karen; Pohlmann, Edward L.; Sheehy, Michael J.; Yang, Ning‐Sun

doi:10.1097/00002371-199903000-00005

Cited by 73 publications

(49 citation statements)

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“…8,9 This antitumor effect is -mediated primarily by CD8 + T cells, which leads to the development of tumorspecific immunological memory. 10 However, from the clinical point of view, this approach is practical only for skin cancers such as melanoma or cutaneous T-cell lymphoma, 8 but not for other types of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 IL-12 gene therapy using gene gun technology has been shown to exhibit a remarkable antitumor effect without toxicity in murine models. 8,9 Rakhmilevich et al reported that transfer of the IL -12 gene into the skin overlying murine tumors using a gene gun effectively eradicates established primary intradermal tumors and their spontaneous metastasis. 10 These antitumor effects are mediated primarily by CD8 + T cells, which lead to the development of tumorspecific immunological memory.…”

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confidence: 99%

“…This IL -12 gene therapy protocol is nontoxic on account of the slow release of transgenic IL -12 protein and, in a comparative study, superior to therapies using other cytokine genes such as interferon ( IFN )-, tumor necrosis factor (TNF ) -, granulocyte -macrophage colony -stimulating factor (GM -CSF ), IL -2, IL -4 or IL-6. 8,9 However, from the clinical point of view, this approach is practical only for skin cancers such as melanoma or cutaneous T-cell lymphoma, 8 but not for other types of cancer.…”

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confidence: 99%

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A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

et al. 2002

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We studied interleukin ( IL ) -12 gene therapy using a gene gun as a new autologous vaccination strategy for cancer. In the first experiment, BALB / c mice were inoculated with syngeneic murine renal cancer cells ( Renca ) intradermally in the abdomen. This was followed by an injection of IL -12 expression plasmid using the gene gun. About 40% of the mice exhibited rejection of the tumor after the treatment and these mice also acquired immunological resistance against a secondary challenge with Renca cells. Based on these results, we examined whether antitumor activity can be potentiated when mice undergo combination treatment with intradermal inoculation of irradiated Renca cells and transfection with IL -12 gene. Inoculation of irradiated Renca cells alone was partially effective in inducing antitumor immunity, whereas the combined treatment remarkably intensified this effect. Moreover, this combined treatment inhibited tumor establishment and enhanced survival of the mice with tumor infiltration by CD4 + and CD8 + T cells, even when the treatment was started after tumor -implantation at a distant site. This antitumor effect was antigen specific and we confirmed the induction of antitumor cytotoxic T cells by this treatment. These results show that local cutaneous transfer of IL -12 expression plasmid using gene gun technology enhances systemic and specific antitumor immunity primed by irradiated tumor cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

et al. 2002

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“…This would circumvent several problems such as systemic toxicity, rapid degradation and the short half-life associated with systemic delivery of various recombinant cytokines. 16 IL-12 is an immune regulatory cytokine, which plays multiple roles in altering the host-tumor relationship, such as: (1) enhancement of the cellular immune mechanism to favor activation and proliferation of CD4 + helper T cells and CD8 + cytotoxic T cells leading to potent Th1 type immune response; (2) recruitment of cytotoxic NK and NKT cells to directly participate in early stages of tumor killing; and (3) up-regulation of endogenous IFN-␥ and TNF-␣, as well as NO to suppress tumor progression, metastasis and angiogenesis. 17 In the present study, we investigated the role of IL-12 gene delivery with a broader perspective, looking into its role in simultaneous induction of various anti-tumoral cytokines, cytotoxic NO, as well as its role in recruitment of various immune cells, which form a part of innate and adaptive immunity, resulting in anti-tumor activity.…”

Section: Discussionmentioning

confidence: 99%

“…20 Low systemic levels of IL-12 have been shown to induce IFN-␥ production and, through feedback control mechanisms, IL-12 would activate its own up-regulation through macrophages, dendritic cells and other stimulatory factors, such as NO induced by IFN-␥ as a part of adaptive immune response. 16,19 We, therefore, determined the induced levels of IFN-␥ and TNF-␣ after intratumoral injection of PAGA/pmIL-12 complexes. The production of both induced cytokines and mIL-12 was significantly up-regulated compared with control mice injected with 5% glucose (Figures 1-3).…”

Section: Discussionmentioning

confidence: 99%

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

et al. 2002

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Natural killer cell depletion confounds the antitumor mechanism of endogenous IL‐12 overexpression

Miller

Bleier

Antonescu

et al. 2004

Intl Journal of Cancer

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IL-12 gene transfer to hepatocytes using a recombinant adenovirus vector (AdIL-12) has been shown to protect against primary and metastatic liver tumors in mice. However, the mechanism of protection has been elusive and studies using depleting monoclonal antibodies or transgenic mice have purported it to be independent of T and NK cells. We postulated that depletion of NK cells may distort the experimental model and misrepresent the antitumor mechanism by altering the magnitude and duration of transgene expression. We show in mice treated with AdIL-12 that NK depletion increased serum IL-12 levels by more than 250-fold and prolonged transgene expression by nearly 2 weeks compared to nondepleted mice. To determine the contribution of NK cells to tumor protection after AdIL-12 treatment, we analyzed NK cells from treated animals. Isolated NK cells were markedly activated in terms of their lytic activity and IFN-␥ secretion. Adoptive transfer of NK cells from mice that had been treated with AdIL-12 to naive mice was sufficient to confer protection against colorectal hepatic metastases. This protection was mediated in part by NK-cell production of IFN-␥. Our findings indicate that NK-cell depletion distorts the model of systemic AdIL-12 administration by markedly altering transgene expression, which then may potentiate other antitumor mechanisms, and that endogenous IL-12 overexpression activates NK cells, rendering them sufficient to protect against liver metastases. These data have critical implications for investigating the immunologic mechanisms of experimental models that utilize gene transfer.

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Gene Gun-Mediated IL-12 Gene Therapy Induces Antitumor Effects in the Absence of Toxicity: A Direct Comparison With Systemic IL-12 Protein Therapy

Cited by 73 publications

References 0 publications

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

Natural killer cell depletion confounds the antitumor mechanism of endogenous IL‐12 overexpression

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