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

点击翻译按钮获取中文摘要

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