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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

法师-1、-2、-3、-4、-6和-12基因在许多不同的癌症中频繁表达，但在除睾丸和胎盘之外的正常细胞或正常组织中不表达。法师-1和-3肽目前被用作癌症患者的疫苗，12名患有转移性黑素瘤的HLA-A1患者中有3名对法师-3肽有应答。因此，法师蛋白有可能成为HLA-A1肿瘤患者的潜在疫苗。然而，在应答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法师疫苗的效力。此外，法师家族蛋白的生物学作用仍有待研究。我们研究了各种癌症患者中法师蛋白家族之一的法师-4蛋白的血清水平。在法师-4^+肿瘤细胞系的上清液和具有不同组织学类型（肺癌、头颈癌和肝细胞癌）的癌症患者的血清中检测到作为非降解形式的法师-4蛋白 ...更多信息 r癌。例如，肺癌患者的法师-4蛋白的血清水平（n=100，平均值= 1.17 ng/ml）显著（p=0.0013）高于患有良性肺病的患者（n=80，平均值= 0.33 ng/ml）或HD患者（n=68，平均值= 0.32 ng/ml）（Shichijo et al.，JJCR，in press，1977）. 100例恶性肿瘤患者中有34例血清法师-4水平高于临界值（1.15ng/ml），其余各组均未达到临界值。在其他癌症患者的血清中也获得了类似的结果。此外，值得注意的是，手术切除肿瘤块导致法师-4蛋白的血清水平降低，并且复发与其再增加有关（Iwamoto等人，Int. J.Cancer，出版中，1997）。此外，血清法师-4在肝细胞癌和丙型肝炎病毒阳性肝硬化患者中显著升高，这是肝细胞癌的高危组。这些信息对于更好地理解法师蛋白的生物学作用可能是重要的，检测法师-4蛋白的血清水平可用于检测不同组织学类型的法师-4^+癌症。在用自体肿瘤细胞或IL-2激活的肿瘤浸润淋巴细胞刺激的外周血单个核细胞（PBMC）的T细胞中观察到HLA I类限制性和肿瘤特异性CTL（TILs）的患者。编码由CTL识别的肽抗原的基因已经使用这些CTL从黑素瘤中克隆。然而，这些CTL或肽抗原的存在很少在腺癌或鳞状细胞癌中报道，这两种主要的人类癌症需要开发新的治疗方式。我们研究了IL-2激活的食管癌、胃癌、结肠癌和肺癌TIL的HLA-A位点限制性和肿瘤特异性。结果显示在食管癌的TIL中存在HLA类限制性和肿瘤特异性CTL（Toh等人，细胞免疫。in Press，1997），胃癌（Hoshino等，Int. J.Cancer in press，1997）、结肠癌（Gouhara等人，JJCR，in press，1997）和非小细胞肺癌（Seki et al.，手机号码出版，1997年）。这些CTL可作为鉴定编码肿瘤排斥抗原的基因的工具，用于开发癌症疫苗。少