| Project/Area Number |
14104013
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
KAWAKAMI Yutaka Keio University, Department of Medicine, Professor, 医学部, 教授 (50161287)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Tomonobu Keio University, Department of Medicine, Instructor, 医学部, 助手 (20199334)
SAKURAI Toshiharu Keio University, Department of Medicine, Instructor, 医学部, 助手 (20101933)
SUMIMOTO Hidetoshi Keio University, Department of Medicine, Instructor, 医学部, 助手 (00306838)
MATSUZAKI Yuriko Keio University, Department of Medicine, Instructor, 医学部, 助手 (40255435)
KUDO Chie Keio University, Department of Medicine, Instructor, 医学部, 助手 (90424126)
塚本 真 慶應義塾大学, 医学部, 助手 (50365441)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥109,590,000 (Direct Cost: ¥84,300,000、Indirect Cost: ¥25,290,000)
Fiscal Year 2006: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
Fiscal Year 2005: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
Fiscal Year 2004: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
Fiscal Year 2003: ¥21,580,000 (Direct Cost: ¥16,600,000、Indirect Cost: ¥4,980,000)
Fiscal Year 2002: ¥29,900,000 (Direct Cost: ¥23,000,000、Indirect Cost: ¥6,900,000)
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| Keywords | Tumor antigens / Immunotherapy / Colon cancer / Pancreas cancer / DNA chip / Tumor markers / Immune escape / Microsatellite instability / 膵癌 / 癌幹細胞 / 樹状細胞 / SEREX / 免疫不全マウス / p53 / 潰瘍性大腸炎 / 癌精巣抗原 / MSI / SCID / K-ras / RDA |
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| Research Abstract |
We have established basics for development of new diagnostic and therapeutic methods for various cancers of digestive organs. 1) Identification of human tumor antigens and individualized immunotherapy : Various tumor antigens and T cell epitopes were identified by using systematic gene analysis and cDNA cloning using human IgG from immunodeficient mice implanted with human cancer tissues. The analysis of the immune responses revealed importance of individualized immunotherapy. Intratumoral administration of peptide pulsed dendritic cells was developed, and it resulted in induction of strong immune responses and anti-tumor effects through antigen spreading. 2) Immune responses to MSI^+ cancers : The immune response to tumor specific frameshift peptides was found to explain good prognosis of patients with MSI^+ cancers, indicating possible immunotherapy to MSI^+ cancers. The immune response to a cancer-testis antigen CAGE was frequently detected in the patients with MSI^+ cancers, sugges
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ting its use in the immunotherapy. 3) Mechanisms for immune escape of cancer cells : Using newly developed mutation specific viral shRNAs, enhanced MAPK signaling through the BRAF or RAS mutation was found to cause production of multiple immunosuppressive factors, indicating immunotherapy in combination with signal inhibitors. 4) Immunological implications of cancer stem cells and epithelial mescenchymal transition (EMT) : Differential expression of tumor antigens in the established stem like pancreatic cancer SP cells and EMT cells was found. EMT was found to enhance tumor metastasis through immunosuppression. 5) Clinical applications of the identified tumor antigens : IgG Abs for tumor antigens were found to be useful for prognostic diagnosis. Anti-p53 Ab was found to be useful for early diagnosis of colon cancer in the patients with ulcerative colitis. Tumor markers useful for diagnosis of high metastatic ability were identified. The identified tumor antigens and immune-interventions are expected to be evaluated in the future clinical trials. KU-CR4 is a potential target for antibody therapy. Less
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