Study of tumor associated antigens recognized by human CD8^+ cytotoxic T lymphocytes

人CD8^细胞毒性T淋巴细胞识别肿瘤相关抗原的研究

• 批准号: 12213134
• 负责人: ITOH Kyogo
• 金额: $ 87.68万
• 依托单位: Kurume University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213134/
• 关键词: Gene; Tumor antigen; Peptide; Immunity; Cytotoxic T lymphocytes; Vaccine; Translational reearch; Personalized medicine; 拒絶抗原; NK細胞; がん; 抗原; アポトーシス; 免疫療法

Research outcome: We made considerable progress in the past five years to identify tumor associated antigens recognized by human CD8+ cytotoxic T lymphocytes (CTL) reactive to cancer cells with an HLA-class I restricted fashion. We have identified more than 100 different tumor-associated antigen genes, along with more than 200 epitopes encoded by these genes, from cDNA of epithelial cancer cells. The majority of these genes encode antigens preferentially expressed in proliferating cells, but not in normal cells at the protein level. These CTL epitope peptides are bound to HLA-A24,-A2 molecules, or those of HLA-A3 family that includes the allelic products of at least five common HLA-A alleles: A3, All, A31, A33, and A68.Some of the peptides mentioned above were provided to phasel /phase II clinical trials as a regimen of personalized peptide vaccination in which pre-vaccination PBMCs were at first screened for their reactivity in vitro to each of the candidate peptides followed by in vi … More vo administration of only the CTL-directed peptides. Adverse effects in this regimen were local skin reactions at the injection sites, and thus this regimen was evaluated as well tolerable. Some types of advanced cancers were sensitive to the personalized peptide vaccination, and they are hormone-refractory prostate cancer, gastric cancer with scirrhous type, cervical cancer, and grade3/4 brain tumors. In contrast, the other cancers were not sensitive to the personalized peptide vaccination under the employed condition, and they are colon cancer, lung cancer, non-scirrhous gastric cancer, melanoma, and pancreatic cancer. It is of note that, in these patients, the overall survival of patients whose sera had increased levels of peptide-reactive IgG (n=60) was significantly more prolonged (p=0.0003) than those who did not (n=31), whereas none of the cellular responses correlated with overall survival. Because of extremely lower survival rate of these diseases, personalized peptide vaccination could be a new treatment modality for advanced anaplastic astrocytoma and glioblastoma. In conclusion, our basic and clinical studies conducted in the past five years could provide novel information in order to develop peptide-based specific immunotherapy for cancer patients. Less

研究成果：在过去的五年中，我们取得了相当大的进展，确定肿瘤相关抗原识别的人CD 8+细胞毒性T淋巴细胞（CTL）反应的癌细胞与HLA-I类限制性的方式。我们已经从上皮癌细胞的cDNA中鉴定了100多种不同的肿瘤相关抗原基因，沿着有200多种由这些基因编码的表位。这些基因中的大多数编码优先在增殖细胞中表达的抗原，但在蛋白质水平上不在正常细胞中表达。这些CTL表位肽与HLA-A24、-A2分子或HLA-A3家族的分子结合，该家族包括至少五种常见HLA-A等位基因的等位基因产物：A3、所有、A31、A33、上述的一些肽作为个性化肽疫苗接种的方案提供给I期/II期临床试验，其中预-首先筛选接种PBMC对每种候选肽的体外反应性，然后进行体内试验。 ...更多信息 vo施用仅CTL指导的肽。该方案的不良反应为注射部位的局部皮肤反应，因此该方案被评价为耐受良好。某些类型的晚期癌症对个性化肽疫苗接种敏感，它们是难治性前列腺癌、硬化型胃癌、宫颈癌和3/4级脑肿瘤。相比之下，其他癌症在所采用的条件下对个性化肽疫苗接种不敏感，并且它们是结肠癌、肺癌、非硬化性胃癌、黑色素瘤和胰腺癌。值得注意的是，在这些患者中，血清中肽反应性IgG水平升高的患者（n=60）的总生存期比血清中肽反应性IgG水平未升高的患者（n=31）显著延长（p=0.0003），而细胞应答均与总生存期无关。由于这些疾病的生存率极低，个性化肽疫苗接种可能是晚期间变性星形细胞瘤和胶质母细胞瘤的一种新的治疗方式。总之，我们在过去五年中进行的基础和临床研究可以提供新的信息，以开发基于肽的特异性免疫治疗癌症患者。少

项目成果

Gene and peptide analyses of newly defined lung cancer rejection antigens recognized by HLA-A2402-restricted tumor-specific cytotoxic T lymphocytes.

HLA-A2402 限制性肿瘤特异性细胞毒性 T 淋巴细胞识别的新定义肺癌排斥抗原的基因和肽分析。

• 发表时间: 2003
• 期刊: Cancer Res 63
• 作者: Yamada A.;Itoh;K.;et al.
• 通讯作者: et al.

Kawamoto N., Itoh K, et al.: "IgG reactive to CTL-directed epitopes of self-antigens is eitherr lacking or unbalanced in atopic dermatitis patients."Tissue Antigen. 62. 352-361 (2003)

Kawamoto N.、Itoh K 等人：“在特应性皮炎患者中，对自身抗原的 CTL 定向表位具有反应性的 IgG 要么缺乏，要么不平衡。”组织抗原。

Harada M., Itoh K., et al.: "Target molecules in specific immunotherapy against prostate cancer."Int.J.Clin.Oncol. 8. 193-199 (2003)

Harada M.、Itoh K. 等人：“针对前列腺癌的特异性免疫疗法中的目标分子。”Int.J.Clin.Oncol。

Shichijo S., Itoh K., et al.: "Identification of two novel tumor-associated antigens recognized HLA-B46-restricted cytotoxic T lymphocytes."Int.J.Mol.Med.. 12. 895-902 (2003)

Shichijo S.、Itoh K. 等人：“识别两种新的肿瘤相关抗原识别 HLA-B46 限制性细胞毒性 T 淋巴细胞。”Int.J.Mol.Med.. 12. 895-902 (2003)

Ohkouchi S., Itoh K., et al.: "Identification of a CTL-directed epitope encoded by an intron of the putative tumor suppressor gene Testin of the common fragile site 7G region : a peptide vaccine candidate for HLA-B52+ and HLA-62+ cancer patients."Eur.J.Im

Ohkouchi S.、Itoh K. 等人：“鉴定由共同脆弱位点 7G 区域的假定肿瘤抑制基因 Testin 的内含子编码的 CTL 定向表位：HLA-B52 和 HLA-B52 的候选肽疫苗