Clinical application and development of DNA vaccine gene immunotherapy targeting MUC1 as tumor antigen

以MUC1为肿瘤抗原的DNA疫苗基因免疫治疗的临床应用及进展

• 批准号: 16591392
• 负责人: TAZUKA Noriaki
• 金额: $ 2.3万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591392/
• 关键词: DNA vaccine; tumor immunotherapy; cytotoxic T cell; helper T cell; MUC1; 細胞傷害性T細胞

Objective. MUC1 DNA vaccine immunotherapy must induce helper and cytotoxic cell-mediated immunity to generate the powerful anti-tumor immune responses needed to suppress cancer progression. We pay attention to MHC class II peptide (Pan-I a peptide) efficiently stimulated T-helper 1 type lymphocytes which was prepared from the pigeon cytochrome c. We investigated whether co-administration of DNA vaccine and dendritic cells pulsed with Pan-I a peptide (DC-IA) can elicit various immunological mechanism and lead to enhancement of anti-tumor immunity in murine model.Results. At first instead of MUC1 we used OVA as tumor antigen, C57BL/6 mice were given an injection of DNA encoding OVA (OVA DNA), and we assayed. 1. OVA DNA vaccines could not suppress tumor growth in mice inoculated with E.G7 generated by transducing the chicken OVA gene into EL4 cells. 2. Although the OVA DNA vaccine elicited significant anti-OVA immunity compared with Mock DNA, there was no difference of cytotoxicity against E.G7 between OVA DNA and Mock DNA. 3. Co-administration of OVA DNA and DC-IA elicited tumor specific cytotoxicity, and suppuresive effects on tumor growth in tumor bearing mouse. 4. Tumor infiltrating IFN-γ producing CD4 or CD8 positive cells were significantly increased in mouse bearing E.G7 tumors by vaccination of OVA DNA and DC-IA compared with that in other groups of mice.Conclusion. Co-administration of DNA vaccine and dendritic cells pulsed with Pan-I a peptide (DC-IA) augemented anti-tumor effects. Now we are investigating this murine model replacing OVA and Pan-I a peptide with MUC1 and Pan-DR peptide (PADRE) that can be presented by various types of mouse and human MHC class II molecules.

Objective. MUC 1 DNA疫苗免疫治疗必须诱导辅助细胞和细胞毒性细胞介导的免疫，以产生抑制癌症进展所需的强大抗肿瘤免疫应答。本研究以鸽细胞色素c为主要抗原，制备了MHC-II类肽（Pan-Ia肽），并对其刺激T辅助细胞1型淋巴细胞的活性进行了研究。我们研究了DNA疫苗和Pan-Ia肽致敏的树突状细胞（DC-IA）联合应用是否能激发多种免疫机制，增强小鼠的抗肿瘤免疫。首先，我们用OVA代替MUC 1作为肿瘤抗原，给C57 BL/6小鼠注射编码OVA的DNA（OVADNA），并进行测定。1.将鸡卵清蛋白基因导入EL 4细胞，经E.G7处理后，接种小鼠，卵清蛋白DNA疫苗不能抑制肿瘤的生长。2.与Mock DNA相比，OVADNA疫苗能诱导小鼠产生显著的抗OVA免疫应答，但对E.G7的细胞毒作用无明显差异。3. OVA-DNA与DC-IA联合应用可引起肿瘤特异性细胞毒作用，并对荷瘤小鼠的肿瘤生长有抑制作用。4.与其他组相比，接种OVADNA和DC-IA的荷E.G7小鼠肿瘤浸润的产生IFN-γ的CD 4或CD 8阳性细胞显著增加。DNA疫苗与Pan-Ia肽致敏的树突状细胞（DC-IA）联合应用可增强其抗肿瘤作用。现在，我们正在研究这种小鼠模型，用MUC 1和Pan-DR肽（PADRE）替代OVA和Pan-I a肽，这些肽可以由各种类型的小鼠和人MHC II类分子呈递。

项目成果

Involvement of 90K/Mac-2 binding protein in cancer metastases by increased cellular adhesiveness in lung cancer.

• DOI: 10.3892/or.12.5.1071
• 发表时间: 2004-11
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: Y. Ozaki;K. Kontani;K. Teramoto;T. Fujita;N. Tezuka;S. Sawai;Toshinaga Maeda;Hiroyoshi Watanabe

Identification of antigenic epitopes recognized by Mac-2 binding protein-specific cytotoxic T lymphocytes for use in cancer immunotherapy.

• DOI: 10.1016/j.bbrc.2004.03.155
• 发表时间: 2004-05
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Y. Ozaki;K. Kontani;K. Teramoto;T. Fujita;N. Tezuka;S. Sawai;Hiroyoshi Watanabe;S. Fujino;T. Asai;I. Ohkubo

Successful tumor eradication was achieved by corroboration of augmented cytotoxic activity and anti-angiogenic effects following therapeutic vaccines containing helper activating analogue loaded dendritic cells and tumor antigen DNA.

通过证实使用含有辅助激活类似物负载树突状细胞和肿瘤抗原DNA的治疗性疫苗后增强的细胞毒活性和抗血管生成作用，成功地消灭了肿瘤。

• 发表时间: 2006
• 期刊: Cancer Immunol Immunother (in press)
• 作者: Koji Teramoto;et al.
• 通讯作者: et al.