Development of cancer vaccine with MAGE gene products.

利用MAGE基因产品开发癌症疫苗。

基本信息

批准号：
07457284
负责人：
ITOH Kyogo
金额：
$ 4.54万
依托单位：
Kurume University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457284/
关键词：
MAGE gene Tumor-rejection antigen Cancer Vaccine Lung Cancer Serum MAGE-4 protein Cancer of digestive tract cytotoxic Tlymphocytes tumor-infiltrating lymphocytes 癌退縮抗原 MAGE HLA-class I拘束性ペプチドワクチン

项目摘要

The MAGE-1, -2, -3, -4, -6, and -12genes are frequently expressed in many different cancers, but are not expressed in normal cells or normal tissues other than testis and placenta. MAGE-1 and -3 peptides are currently used as vaccines for cancer patients, and three of 12 HLA-A1 patients with metastatic melanoma responded to MAGE-3 peptide. Therefore, MAGE protein could be a potential vaccine for HLA-A1 cancer patients. However, CTL were not detected in the peripheral blood of the responding patients, and there was no available monitoring methods to know the efficacy of MAGE vaccine. Further, biological roles of proteins of MAGE family remain to be investigated. We investigated serum level of MAGE-4 protein, one of the family of MAGE proteins, in various cancer patients. MAGE-4 protein was detected as a non-degraded form in both the supernatant of MAGE-4^+ tumor cell line and serum of cancer patients with different types of histology (lung cancer, head and neck cancer, and hepatocellula … More r carcinomas. For example, serum level of the MAGE-4 protein of lung cancer patients (n=100, mean=1.17ng/ml) was significantly (p=0.0013) higher than that of either patients with benign pulmonary diseases (n=80, mean=0.33ng/ml) or HD (n=68, mean=0.32ng/ml) (Shichijo et al., JJCR,in press, 1977). The serum level of MAGE-4 was higher than the cutoff level (1.15ng/ml) in 34 of 100 cancer patients, but no one in the other groups reached the cutoff level. The similar results were obtained in sera of the other cancer patients. In addition, it is of note that surgical removal of tumor mass resulted in decrease of serum level of MAGE-4 protein and recurrence was associated with it's reincrease (Iwamoto et al., Int. J.Cancer, in press, 1997). Furthermore, serum MAGE-4 was significantly higher in patients with both hepatocellular carcinoma and hepatitis C virus positive liver cirrhosis, a high risk group of hepatocellular carcinoma. These information could be important for better understanding of biological roles of MAGE proteins, and measurement of serum levels of MAGE-4 protein could be useful for detection of MAGE-4^+ cancers with different types of histology.HLA class I-restricted and tumor-specific CTLs have been observed in T cells of peripheral blood mononuclear cells (PBMC) stimulated with autologous tumor cells or IL-2-activated tumor infiltrating lymphocytes (TILs) of patients with melanomas. Genes encoding peptide antigens recognized by CTLs have been cloned from melanomas using these CTLs. However, either the presence of these CTLs or peptide antigens have been rarely reported in either adenocarcinoma of squamous cell carcinoma, two major human cancers needed for development of new treatment modalities. We have investigated HLA-A locus-restriction and tumor-specificity of IL-2 activated TILs from esohageal cancers, gastric cancers, colon cancers and lung cancers. The results showed the presence of HLA class lredtricted and tumor specific CTLs in TILs of esophageal cancers (Toh et al., Cell lmmunol. in press, 1997), gastric cancers (Hoshino et al., Int. J.Cancer in press, 1997), colon cancers (Gouhara et al., JJCR,in press, 1997) and non-small lung cancers (Seki et al., Cell lmmunolo. in press, 1997). These CTLs could be a tool for identification of genes encoding tumor-rejection antigens for development of cancer vaccines. Less

MAGE-1、-2、-3、-4、-6 和 -12 基因在许多不同的癌症中频繁表达，但在正常细胞或除睾丸和胎盘之外的正常组织中不表达。肽目前被用作癌症患者的疫苗，12名HLA-A1转移性黑色素瘤患者中有3名对MAGE-3肽有反应，因此，MAGE蛋白可能是HLA-A1癌症患者的潜在疫苗。然而，在有反应的患者的外周血中未检测到CTL，并且没有可用的监测方法来了解MAGE疫苗的功效。此外，我们还研究了MAGE家族蛋白的生物学作用。 -4蛋白是MAGE蛋白家族之一，在多种癌症患者的MAGE-4^+肿瘤细胞系上清液和不同类型癌症患者的血清中均检测到未降解的形式。组织学的例如，肺癌患者的血清MAGE-4蛋白水平（n=100，平均值=1.17ng/ml）显着高于（p=0.0013）。良性肺部疾病患者（n=80，平均值=0.33ng/ml）或HD患者（n=68，平均值=0.32ng/ml）（Shichijo等人， JJCR，出版中，1977）。100 名癌症患者中，有 34 名患者的 MAGE-4 血清水平高于临界水平（1.15ng/ml），但其他组中没有人达到临界水平。此外，值得注意的是，手术切除肿瘤块导致血清 MAGE-4 蛋白水平降低，复发与其重新增加相关（Iwamoto）。等人，Int. J.Cancer，出版中，1997）此外，肝细胞癌和丙型肝炎病毒阳性肝硬化患者（肝细胞癌的高危人群）的血清 MAGE-4 显着升高。更好地了解 MAGE 蛋白的生物学作用，测量 MAGE-4 蛋白的血清水平可能有助于检测不同组织学类型的 MAGE-4^+ 癌症。HLA 类别在用自体肿瘤细胞或黑色素瘤患者的 IL-2 激活的肿瘤浸润淋巴细胞 (TIL) 刺激的外周血单核细胞 (PBMC) 的 T 细胞中观察到 I 限制性和肿瘤特异性 CTL 编码肽抗原的基因。已经使用这些CTL从黑色素瘤中克隆了CTL，然而，在腺癌或腺癌中很少报道这些CTL或肽抗原的存在。鳞状细胞癌是开发新治疗方法所需的两种主要人类癌症，我们研究了来自食管癌、胃癌、结肠癌和肺癌的 IL-2 激活 TIL 的 HLA-A 位点限制和肿瘤特异性。食管癌 TIL 中存在 HLA 类限制性和肿瘤特异性 CTL（Toh 等人，Cell Immunol. in press， 1997)、胃癌(Hoshino et al., Int. J.Cancer in press, 1997)、结肠癌(Gouhara et al., JJCR,in press, 1997)和非小细胞肺癌(Seki et al., Cell) lmmunolo. 出版，1997）。这些 CTL 可以作为鉴定编码肿瘤排斥抗原的工具，用于开发癌症疫苗。