Non-viral delivery of interleukin-2 and soluble Flk-1 inhibits metastatic and primary tumor growth in renal cell carcinoma

Yockman, James W.; Kim, Won Jong; Chang, Chien‐Wen; Kim, Sung Wan

doi:10.1038/sj.gt.3302999

Cited by 11 publications

(6 citation statements)

References 26 publications

(26 reference statements)

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“…In many studies, Renca cells are injected s.c. to produce localized tumors or intravenously (i.v.) to produce experimental lung metastases [29], [30], [31], [32], [33]. We had previously shown that intratumoral administration of Ad5mTRAIL plus CpG1826 could lead to the eradication of localized s.c. Renca tumors in mice [16].…”

Section: Resultsmentioning

confidence: 99%

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

et al. 2012

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Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC.

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Section: Resultsmentioning

confidence: 99%

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

et al. 2012

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“…Many investigators believe that PEI‐based DNA transfer systems are well suited for use in gene therapy for the treatment of cancer. ( 3,31–34 ) Although PEI has been proven to be effective in gene delivery due to its condensation of DNA, it is not biodegradable. Moreover, the improvement of transfection efficiency is accompanied by increased cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis

Zhou

Gou

et al. 2011

Cancer Science

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Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-a and interferon-c in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. (Cancer Sci 2011; 102: 1403-1409 L ung metastasis is the most common cause of cancer death in both men and women. Investigators have done a lot to improve its prognosis and the development of new modalities of treatment. Gene therapy is a promising and powerful method; currently, its potential in cancer treatment is widely recognized. However, the major limitation of gene therapy of the lung is the low efficiency of gene transfer and the technical difficulties of regimen delivery.(1) Delivery vectors play an important role in gene therapy because the plasmid DNA must be protected from damage and its entry into the cell must be facilitated. Some polymers and cationic lipids have shown high gene transfection efficiency in the lung for DNA encapsulated.(2) The cationic polymer polyethylenimine (PEI) has the ability to protect DNA from undesirable degradation during the transfection process and is one of the most effective non-viral gene vectors. (3)(4)(5) However, PEI also has a shortcoming: the increase in transfection efficiency is accompanied by an increase in cytotoxicity, and both efficiency and cytotoxicity increase as its molecular weight increases. To address this challenge, we used heparin to couple PEI together, forming HPEI nanogels; these nanogels had high transfection efficiency and low toxicity, showing promising application as a non-viral gene delivery system. (6) Interleukin-15 (IL15) is a cytokine first identified in the supernatant of the monkey epithelial cell line CV-1 ⁄ EBNA and has a simila...

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“…The use of this polymer has been used to deliver genes to several different cancers, myocardium and corpus cavernosum. [45][46][47][48][49] In summary, we have demonstrated that ischemiainducible VEGF gene therapy improves the efficacy of VEGF gene therapy for myocardial infarction through decreased apoptosis and increased angiogenesis.…”

Section: Ischemia-inducible Gene Therapy Jw Yockman Et Almentioning

confidence: 89%

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

et al. 2008

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Non-viral delivery of interleukin-2 and soluble Flk-1 inhibits metastatic and primary tumor growth in renal cell carcinoma

Cited by 11 publications

References 26 publications

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

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