1994 Fiscal Year Final Research Report Summary
A STUDY ON IMMUNOTHERAPY OF ORAL CANCERS
| Project/Area Number |
04404077
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
外科・放射線系歯学
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| Research Institution | TOKYO MEDICAL AND DENTAL UNIVERSITY |
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Principal Investigator |
FUJIBAYASHI Takashi Tokyo Medical and Dental University, The Second Dept.of Oral & Maxillofacial Surgery, Associate Professor, 歯学部, 助教授 (80013978)
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| Co-Investigator(Kenkyū-buntansha) |
AZUMA Miyuki Juntendou University, Department of Immunology, Resaerch Associate, 医学部, 助手 (90255654)
KAMATA Nobuyuki Same with the above institution and department, Research Associate, 歯学部, 助手 (70242211)
ISHII Masatoshi Same with the above institution and department, Research Associate, 歯学部, 助手 (70212826)
TAKAHASHI Yuzo Tokyo Medical and Dental University, The Second Dept.of Oral & Maxillofacial Sur, 歯学部, 講師 (50014329)
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| Project Period (FY) |
1992 – 1994
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| Keywords | oral cancer / OK-432 / LAK cells / adoptive immunotherapy / chemotherapeutic agents / co-stimulatory signal / CD80 / CD86 |
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| Research Abstract |
Cell-mediated immunity of oral cancer patients in terms of peripheral blood lymphocytes, CD3^+, CD4^+, CD8^+, CD4/CD8 ratio, and so on were compared between patients with tumor recurrence and patients without recurrence. Tumor recurrence group showed significant decrease in cell-mediate immunity. Then, Thirty-one oral cancer patients who received immunotherapy by OK-432 were examined and compared with 23 control patients who received no immunotherapy. Decrease of CD3^+ cells and CD4^+ cells due to cancer treatments was inhibited by OK-432 immuno-therapy, and inhibitory effect on decrease of NK activity during cancer treatments was also recognized in the immunotherapy group. Not only single BRM therapy such as OK-432 but also the therapeutic efficacy of adoptive immunotherapy with the adoptive transfer of autologous LAK cells plus recombinant interleukin-2 (rlL-2) activated with anti-CD3 monoclonal antibody and rlL-2 was investigated in oral cancer patients. Although cytotoxic activity
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of single CD3/LAK cells induced by solid phase anti-CD3 monoclonal antibody plus rlL-2 showed lower than that of LAK cells activated by single rlL-2, total lytic activity of whole culture of CD3/LAK cells showed greater because of vigorous proliferation of CD3/LAK cells.
To improve the therapeutic efficacy of adoptive immunotherapy by CD3/LAK cells, the effect of the combination therapy of CD3/LAK and chemo-therapy or administration of other cytokines was investigated. Pretreatments of target cultured cell lines established from oral cancer cells with chemotherapeutic agents such as CDDP,5-FU increased cytotoxic activity of CD3/LAK cells. In contrast, pretreatments of the target cells with IFN-gamma, TNF-alpha decreased the cytotoxic activity of CD3/LAK cells. By combination of pretreatment of IFN-gamma and CDDP or 5-FU the decrease of the cytotoxic activity of CD3/LAK cells by IFN-gamma was reduced in resulting compensation of the cytotoxic activity.
Recent immunological studies have revealed that both specific ligand and co-stimulatory signals such as CD28 on T cells and CD80, CD86 on APC are required for the induction, activation and clonal expansion from naive T cells to active CTL.Although active B cells, macrophages, and professional APC such as dendolitic cells were expressing CD80, CD86, almost all tumor cells showed no expression of them. The experimental animal model of CD80 gene transfection to CD80 negative mice fibrosarcoma cell line (Meth A) showed rejection of growth of Meth A in syngenic mice. The immunologic specificity of Meth A specific rejection indicted that tumor specific CTL is induced by this gene therapy. Less
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