| Project/Area Number |
15590812
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | The University of Tokushima |
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Principal Investigator |
NISHIOKA Yasuhiko The University of Tokushima, Institute of Health Biosciences, assistant professor, 大学院・ヘルスバイオサイエンス研究部, 講師 (70274199)
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| Co-Investigator(Kenkyū-buntansha) |
YANAGAWA Hiroaki The University of Tokushima, University Medical and Dental Hospital, associate professor, 医学部・歯学部附属病院, 助教授 (50263827)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | lung cancer / specific immunotherapy / mature dendritic cells / MAGE-3 / cancer vaccine / OK-432 |
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| Research Abstract |
Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs pulsed with peptides of tumor-associated antigens (TAA) have been used in cancer immunotherapy. An early clinical study demonstrated the safety of these trials, but the clinical effect was not sufficient. Most studies have used immature DCs generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Here, we conducted phase I clinical trial of active immunotherapy using mature DCs induced by a streptococcus derivatives OK-432. DCs were generated from blood monocytes by culturing with GM-CSF and IL-4 for 6 days and then GM-CSF,IL-4 and OK-432 for 2 days. Before injection, DCs were pulsed with MAGE-3 peptide (IMPKAGLLI), which is restricted for HLA-A^*2402, and keyhole limpet hemocyanin (KLH) as a control antigen. We selected HLA-A^*2402-positive patients who had advanced solid tumors expressing MAGE-3 mRNA. DC vaccine was administered subcutaneou
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sly every 2 weeks for a total of four vaccinations in a dose-escalation design at the dose level per cohort of 0.1 (Group 1),0.3 (Group 2) and 1 (Group 3) x 10^8 DCs/injection. Three patients were enrolled in each group. Immunological monitoring with delayed type hypersensitivity (DTH) reaction and MHC tetramer was performed. This protocol was well tolerated. A mild fever (Grade 1 to 2) and local reaction of injection site (erythema and induration : Grade 1) were found in all patients. DTH for MAGE-3 peptide became to be positive in the earlier period when a high dose of DCs was administered. 1 x 10^8 DCs/injection was most effective to induce a positive DTH reaction. The decrease of tumor marker (CEA) was found in one patient. One patient showed the stable disease (SD) for four months, but others were progressive. These results indicated that vaccination with mature DCs was safe and feasible, but further studies were required to obtain the objective clinical responses.
To enhance the clinical effects of DC vaccine, one of the approaches was to find the novel tumor antigen expressing in lung cancer which more effectively induce tumor specific immunity. We found the candidate for these tumor antigens, HM1.24 antigen. Furthermore, we identified the tumor peptide of HM1.24 antigen which are restricted to HLA-A24 and can induce cytotoxic T lymphocytes. The clinical trial using HM 1.24 peptide was expected. Less
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