A STUDY ON IMMUNOTHERAPY OF ORAL CANCERS

口腔癌免疫治疗的研究

• 批准号: 04404077
• 负责人: FUJIBAYASHI Takashi
• 金额: $ 5.76万
• 依托单位: TOKYO MEDICAL AND DENTAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04404077/
• 关键词: oral cancer; OK-432; LAK cells; adoptive immunotherapy; chemotherapeutic agents; co-stimulatory signal; CD80; CD86; LAK療法; 免疫能; costimulatory分子; CD28; 化学療法剤処理; サイトカイン; B7; BB1; B70; IL-2(インターロイキン2); 養子兔疫療法; OK-432; 主要組織適合抗原; TIL(腫瘍組織浸

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 … More 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

比较复发与未复发口腔癌患者外周血淋巴细胞、CD 3 ^+、CD 4 ^+、CD 8 ^+、CD 4/CD 8比值等细胞免疫功能的变化。肿瘤复发组细胞免疫功能明显下降。然后，对31例接受OK-432免疫治疗的口腔癌患者进行了检查，并与23例未接受免疫治疗的对照患者进行了比较。OK-432免疫治疗抑制了癌症治疗导致的CD 3 ^+细胞和CD 4 ^+细胞的减少，并且在免疫治疗组中也认识到了对癌症治疗期间NK活性降低的抑制作用。在口腔癌患者中，不仅研究了单一BRM治疗如OK-432，而且还研究了过继免疫治疗的疗效，过继免疫治疗包括自体LAK细胞过继转移加用抗CD 3单克隆抗体和rIL-2激活的重组白细胞介素-2（rIL-2）。虽然细胞毒活性 ...更多信息 CD 3/LAK细胞增殖旺盛，诱导的单个CD 3/LAK细胞的总杀伤活性低于单个rIL-2激活的LAK细胞，为提高CD 3/LAK细胞过继免疫治疗的疗效，观察CD 3/LAK细胞联合化疗或其他细胞因子治疗的效果。用CDDP、5-FU等化疗药物预处理口腔癌细胞建立的靶向培养细胞系，可提高CD 3/LAK细胞的杀伤活性。而IFN-γ、TNF-α预处理靶细胞则可降低CD 3/LAK细胞的杀伤活性。IFN-γ联合CDDP或5-FU预处理可减轻IFN-γ对CD 3/LAK细胞杀伤活性的降低，使其杀伤活性得到补偿，近年来的免疫学研究表明，IFN-γ的诱导需要特异性配体和共刺激信号，如T细胞表面的CD 28和APC表面的CD 80、CD 86，尽管活化的B细胞、巨噬细胞和专职APC如树突状细胞表达CD 80、CD 86，但几乎所有肿瘤细胞均不表达。将CD 80基因转染到CD 80阴性小鼠纤维肉瘤细胞系（MethA）的实验动物模型显示，MethA在同基因小鼠中的生长被排斥。甲硫氨酸特异性排斥反应的免疫学特异性表明该基因治疗诱导了肿瘤特异性CTL。少

项目成果

Miyuki Azuma, Daisuke Ito, Hideo Yagita, Ko Okumura, Joseph H.Phillips, Lewis L.Lanier and Chamorro Somoza: "B70 antigen is a second ligand for CTLA-4 and CD28." Nature. 366. 76-79 (1993)

Miyuki Azuma、Daisuke Ito、Hideo Yagita、Ko Okumura、Joseph H.Phillips、Lewis L.Lanier 和 Chamorro Somoza：“B70 抗原是 CTLA-4 和 CD28 的第二个配体。”

藤林孝司、後藤聡、高橋雄三、森 良之、湊 秀次、榎本昭二: "口腔領域悪性腫瘍患者の細胞性免疫能に対するOK-432の効果" Biotherapy. 7. 158-166 (1993)

Koji Fujibayashi、Satoshi Goto、Yuzo Takahashi、Yoshiyuki Mori、Hidetsugu Minato、Shoji Enomoto：“OK-432 对口腔恶性肿瘤患者细胞介导免疫的影响”生物治疗 7. 158-166 (1993)。

藤林孝司ら: "口腔領域悪性腫瘍患者の細胞性免疫能に対するOK-432の効果" Biotherapy. 7. 158-166 (1993)

Takashi Fujibayashi 等人：“OK-432 对口腔恶性肿瘤患者细胞免疫的影响”生物疗法 7. 158-166 (1993)。

湊 秀次 ほか: "化学療法剤処理口腔扁平上皮癌由来細胞株のLAK感受性と細胞膜抗原" 第38回日本口腔外科学会総会抄録集. 193-193 (1993)

Hidetsugu Minato 等：“化疗治疗的口腔鳞状细胞癌细胞系的 LAK 敏感性和细胞膜抗原”日本口腔颌面外科学会第 38 届年会记录 193-193（1993）。

藤林孝司、後藤聡、高橋雄三、森 良之、湊 秀次、榎本昭二: "口腔領域悪性腫瘍患者再発症例の細胞性免疫能に関する研究" Biotherapy. 7. 150-157 (1993)

Koji Fujibayashi、Satoshi Goto、Yuzo Takahashi、Yoshiyuki Mori、Hidetsugu Minato、Shoji Enomoto：“复发性口腔恶性肿瘤患者细胞免疫功能的研究”生物治疗7. 150-157 (1993)。