| Project/Area Number |
13357009
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Hematology
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| Research Institution | Mie University |
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Principal Investigator |
SHIKU Hiroshi Mie University, Faculty of Medicine, Professor, 医学部, 教授 (80154194)
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| Co-Investigator(Kenkyū-buntansha) |
AKIYOSHI Kazunari Tokyo Medial and Dental University, Institute of Biomaterials and Bioengineering, Professor, 生体材料工学研究所, 教授 (90201285)
KATAYAMA Naoyuki Mie University Hospital, Assistant Professor, 医学部附属病院, 講師 (20185812)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥50,570,000 (Direct Cost: ¥38,900,000、Indirect Cost: ¥11,670,000)
Fiscal Year 2003: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
Fiscal Year 2002: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2001: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000)
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| Keywords | oncogene / killer T cells / helper T cells / polyvalent cancer vaccine / HER2 / 癌ワクチン / ペプチド / CTLエピトープ / ヘルパーエピトープ |
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| Research Abstract |
Recognition of the essential role of dendritic cells (DC) as professional antigen-presenting cells has prompted investigators to search for methods to use DC as natural adjuvants in immunotherapy. A number of antigenic oligopeptides recognized by CD8^+ cytotoxic T lymphocytes (CTL) specific for cancer cells have been applied in clinical trials using DC. Such monovalent vaccine with a single epitope for a particular type of HLA class I molecule would be effective. However, a polyvalent vaccine might be more potent. We designed a novel protein delivery system consisting of hydrophobized polysaccharides complexed with target proteins. The truncated HER2 protein encompassing 146 N-terminal amino acids, including the 9-mer Her2p63-71 peptide (Her2p63), TYLPTNASL, the human homologue of an antigenic murine tumor rejection peptide, was prepared. HLA-A2402^+DC could incorporate hydrophobized polysaccharide/truncated HER2 Protein complexes and process the protein to present MHC class I-binding HER2p63 peptide. The complexes enter DC by phagocytosis and then the truncated protein is processed through the pathway similar to endogenous proteins. DC sensitized by these complexes primed and boosted HER2p63-specific CD8^+ T cells in the context of HLA-A2402. Vaccination with DC incorporating these complexes completely suppressed lung metastases in a HER2-expressing murine tumor model. We also generated three CD4^+ clones reactive with different HER2-derived 25-mer peptides, from lymph node cells in mice treated with CHP/HER2-146. Thus, hydrophobized polysaccharide/protein complexes are promising candidates for the construction of polyvalent vaccines. Phase I clinical trial with CHP/HER2-146 is ongoing in Mie University Hospital.
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