Development of cancer vaccine with MAGE gene products.

利用MAGE基因产品开发癌症疫苗。

• 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; 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

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经常表达，但在睾丸和斑点以外的正常细胞或正常组织中不表达。 MAGE-1和-3辣椒目前被用作癌症患者的疫苗，而转移性黑色素瘤的12例HLA-A1患者中有3例对Mage-3 Pepperide有反应。因此，MAGE蛋白可能是HLA-A1癌症患者的潜在疫苗。但是，在反应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有效性。此外，法师家族蛋白质的生物学作用仍有待研究。我们研究了各种癌症患者的Mage-4蛋白的血清-4蛋白水平，这是法师蛋白的家族之一。 MAGE-4蛋白在MAGE-4^+肿瘤细胞系的上清液中被检测为一种非缩减形式，并且具有不同类型的组织学类型的癌症患者的血清（肺癌，头颈癌，头颈癌和肝素……更多R carcinomas。 （p = 0.0013）高于良性肺部疾病的患者（n = 80，平均= 0.33ng/ml）或HD（n = 68，平均值= 0.32ng/ml）（Shichichijo等人，JJCR，JJCR，在Press，1977年度均高于100 call and carly call carly carly carter-n in carly carly carly noceft carl。其他组在其他癌症患者的血清中获得了相似的结果，因此，肿瘤质量的手术清除导致Mage-4蛋白质的血清水平降低，并且复发与其重新酶相关（癌和丙型肝炎病毒阳性肝硬化，这是肝细胞癌的高风险组。这些信息对于更好地理解MAGE蛋白的生物学作用可能很重要，并且对MAGE-4蛋白的血清水平的测量对于检测具有不同类型的组织学类型的MAGE-4^+癌症。黑色素瘤患者的肿瘤浸润淋巴细胞（TILS）。使用这些CTL从黑色素瘤克隆了编码由CTL识别的肽抗原的基因。但是，要么存在这些CTL或胡椒抗原的存在，我们很少在鳞状细胞癌的腺癌中报道过，这是开发新治疗方式所需的两种主要人类癌。我们已经研究了来自Esohageal癌，胃癌，结肠癌和肺癌的IL-2激活TIL的HLA-A基因座和肿瘤特异性。 The results showed the presence of HLA class lredtric 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。，lmmunolo。这些CTL可以是鉴定编码癌症疫苗开发肿瘤抑制抗原的基因的工具。较少的