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

研究成果：在过去的五年中，我们在人类CD8+细胞毒性T淋巴细胞（CTL）识别肿瘤相关抗原方面取得了相当大的进展，这些抗原以hla - I类限制性方式对癌细胞产生反应。我们已经从上皮癌细胞的cDNA中鉴定出100多个不同的肿瘤相关抗原基因，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抗原优先在增殖细胞中表达，而不是在正常细胞的蛋白质水平上表达。这些CTL表位肽与HLA-A24、-A2分子或HLA-A3家族的分子结合，其中包括至少五种常见HLA-A等位基因的等位基因产物：A3、All、A31、A33和A68。上面提到的一些肽被提供给II期临床试验，作为个性化肽疫苗接种方案，其中接种前pbmc首先在体外筛选其对每种候选肽的反应性，然后在体外筛选其对ctl定向肽的反应性。该方案的副作用是注射部位的局部皮肤反应，因此该方案被评估为可耐受。个体化肽疫苗对部分晚期肿瘤敏感，包括激素难治性前列腺癌、肝硬化型胃癌、宫颈癌和3/4级脑肿瘤。相比之下，在就业条件下，其他癌症对个性化肽疫苗接种不敏感，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（p=0.0003）明显长于血清中肽反应性IgG水平升高的患者（n=31），而细胞反应与总生存期无关。由于这些疾病的生存率极低，个性化肽疫苗接种可能成为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为开发基于肽的癌症患者特异性免疫治疗提供新的信息。少

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