2011 Fiscal Year Final Research Report
Development of"immunostimulatory virotherapy"to treat various malignancies
| Project/Area Number |
21390364
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
UEDA Yasuji 千葉大学, 医学研究院, 客員准教授 (80165662)
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| Co-Investigator(Renkei-kenkyūsha) |
MAEHARA Yoshihiko 九州大学, 医学研究院, 教授 (80165662)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 実験外科学 |
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| Research Abstract |
Though DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, its clinical efficacies are still insufficient in many human trials. Especially, malignant ascites(MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers.
First, floating cultivation of mononuclear cells from cancer patients under an optimized cytokine cocktail(GM-CSF/SCF) led these cells to stable proliferation and to DC differentiation. As are seen in conventional DCs, expanded DCs showed dendrites after maturation, and endocytotic activities. Expanded DCs also expressed HLA-DR, adhesion molecules, and co-stimulatory molecules and produced inflammatory cytokines as well as conventional DCs did. Functionally, MLR assay revealed that expanded DCs could stimulate allogenic T-cell proliferation to the same extent as conventional DCs.
Next, using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A and its decoy receptor, soluble fms-like tryrosine kinase receptor-1(sFLT-1), was a major cause of MA resistance to DC-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene. deleted recombinant Sendai virus(rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors.
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[Journal Article] Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites2011
Author(s)
Sugiyama M, Kakeji Y, Tsujitani S, Harada Y, Onimaru M, Yoshida K, Tanaka S, Emi Y, Morita M, Morodomi Y, Hasegawa M, Maehara Y, Yonemitsu Y.
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Journal Title
Mol Cancer Ther
Volume: 10
Pages: 540-549
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