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

研究结果：在过去的五年中，我们取得了长足的进步，以鉴定由人CD8+细胞毒性T淋巴细胞（CTL）识别的肿瘤抗原，并以HLA级I限制了时尚对癌细胞的反应。我们已经确定了100多种不同肿瘤相关的抗原，以及来自上皮癌细胞cDNA的200多个由这些基因编码的表位。这些基因的大多数编码在增殖细胞中优先表达的抗原，但在蛋白质水平的正常细胞中不表达。这些CTL表位宠物与HLA-A24，-a2分子或HLA-A3家族的hla-A2分子约束，其中包括至少五个常见的HLA-A-A等位基因的等位基因产品：A3，All，All，All，All，A31，A33和A68。首先，PBMC在体外对每种候选肽的反应性进行了筛选，然后在VI中进行筛选…仅对CTL定向肽的VO给药。该方案中的不良反应是注射部位的局部皮肤反应，因此可以评估该方案。某些类型的晚期癌症对个性化的肽疫苗敏感，它们是难治性的前列腺癌，具有Scirrhous类型的胃癌，宫颈癌和3级/4级脑肿瘤。相比之下，其他癌症在员工状况下对个性化肽疫苗不敏感，它们是结肠癌，肺癌，非肝硬化胃癌，黑色素瘤和胰腺癌。值得注意的是，在这些患者中，血清的总体存活率比没有（n = 31）的患者延长了肽反应性IgG水平（n = 60）的延长（p = 0.0003），而细胞反应与总体存活率没有相关的患者（n = 31）。由于这些疾病的存活率极低，个性化的肽疫苗接种可能是晚期构型星形胶质细胞瘤和胶质母细胞瘤的一种新治疗方式。总之，过去五年进行的我们进行的基本和临床研究可以提供新的信息，以开发基于肽的癌症患者的特异性免疫疗法。较少的

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.

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.

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。