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：过去五年，我们在鉴定人类 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 识别的肿瘤相关抗原方面取得了相当大的进展，这些抗原与 HLA-I 类限制性癌细胞反应。我们已经鉴定了 100 多种不同的肿瘤相关抗原。来自上皮癌细胞 cDNA 的抗原基因以及由这些基因编码的 200 多个表位。这些基因中的大多数编码优先在增殖细胞中表达的抗原，但在正常细胞中不表达该蛋白。这些 CTL 表位肽与 HLA-A24、-A2 分子或 HLA-A3 家族的分子结合，其中 HLA-A3 家族包括至少五个常见 HLA-A 等位基因的等位基因产物：A3、A11、A31、A33 和 A68。上述一些肽作为个性化肽疫苗接种方案提供给 II 期临床试验，其中首先筛选疫苗接种前的 PBMCs该方案的不良反应是注射部位的局部皮肤反应，因此该方案被评估为可耐受的。晚期癌症类型对个性化肽疫苗接种敏感，其中包括激素难治性前列腺癌、硬质型胃癌、宫颈癌和3/4级脑肿瘤，而其他癌症则对个性化肽疫苗不敏感。在使用条件下进行个体化肽疫苗接种，它们是结肠癌、肺癌、非硬性胃癌、黑色素瘤和胰腺癌，值得注意的是，在这些患者中，血清中肽水平升高的患者的总体生存率。肽反应性 IgG (n = 60) 比那些没有肽反应性 IgG (n = 31) 的人 (n = 31) 显着延长 (p = 0.0003)，而没有任何细胞反应与总生存率相关。总之，我们在过去五年中进行的基础和临床研究可以为癌症患者开发基于肽的特异性免疫疗法提供新的信息。较少的

项目成果

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。

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。

Maeda Y., Itoh K., et al.: "Cleavage and polyadenylation specificity factor (CPSF)-derived peptides can induce HLA-A2-restriceted and tumor-specific CTLs in the majority of gastrointestinal cancer patients"Int. J. Cancer. 99. 409-417 (2002)

Maeda Y.、Itoh K. 等人：“裂解和聚腺苷酸化特异性因子 (CPSF) 衍生的肽可以在大多数胃肠道癌症患者中诱导 HLA-A2 限制性和肿瘤特异性 CTL”。

Gohara R., Itoh K., et al.: "Phase I Clinical Study of Cyclophilin B Peptide Vaccine for patients with Lung Cancer"J. Immuotherapy. 25. 439-444 (2002)

Gohara R.，Itoh K.，等：“亲环素 B 肽疫苗治疗肺癌患者的 I 期临床研究”J.