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
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.
MAGE-4抗原に対する特異的モノクローナル及びポリクローナル抗体を作製し、それらによるELISAを用いて癌組織及び癌患者血清中MAGE-4抗原の定量化に成功した(Shichijo et al.,J.Immunol.Meth.186,137-149,1995)。同ELISAは、癌組織では10pg/mg,血中では1ng/mlレベルのMAGE-4抗原を特異的に定量可能であり、きわめて高い感度と考えられる。同ELISAにより、癌患者血中レベルで有意に高い症例は肺癌では40%、頭頚部扁平上皮癌では45%、食道癌の消化器癌に35%と高値を示した(Shichijo et al,JJCR,87,751-756,1996)。また肝癌患者血清においてもMAGE-4値は有意に高いのみならず肝癌リスクの高いC型肝炎ウイルス陽性肝硬変患者血中MAGE-4値も高値を示した。一方アルコール性肝硬変やB型肝炎ウイルス陽性肝硬変患者血中MAGE-4値の上昇は認められなかった。これらより血中MAGE-4値の測定は肝癌(C型ウイルス陽性)の早期診断にも有用と考えられた。
血中MAGE-4抗原レベルは術後癌消失に伴ってすみやかに正常化する。さらに、極く初期の癌を有する患者においても高値を示す場合が多く、早期診断の有用な手術をなりえることを明らかにした(Iwamoto,et al.,Int.J.Cancer,in press,1997)。本法の開発はMAGE癌ワクチンの対象者を決定する重要な検査法となると考えられる。 Less