Identification of new lung cancer antigens and development of peptide vaccine

我们克隆了6个肿瘤抗原基因，并对其中10个由细胞毒性T淋巴细胞识别的表位多肽进行了鉴定。它们不仅在肺癌中表达，而且在其他腺癌和鳞癌中也有表达，表达水平相对较高。因此，作为翻译研究，我们对包括肺癌、结肠癌、胃癌、胰腺癌、前列腺癌和恶性脑肿瘤在内的各种癌症患者进行了个性化多肽疫苗的临床试验，共178例，使用这些表位多肽和先前确定的多肽。注射部位的局部炎症经常被观察到，然而，除了一些病例的发热(CTCAE版本3的2级)外，没有检测到全身不良事件。这些结果表明，个性化多肽疫苗是安全的。这些疫苗的抗肿瘤效果在恶性胶质母细胞瘤患者中得到证实。在激素难治性前列腺癌的病例中，疫苗和小剂量磷酸雌二醇的联合治疗显示了临床效果。由于一些疫苗多肽在预防皮试中会立即引起过敏样皮肤反应，因此在动物模型中研究了这种反应的确切机制。多肽诱导的皮肤反应是由肥大细胞脱颗粒引起的，其机制不依赖抗体。然而，由于疫苗多肽在血浆中的快速降解，肥大细胞的这种脱颗粒不会引起全身过敏反应。这一现象与多肽疫苗的抗癌效果无关。我们还通过系统诱导的CTL在肿瘤部位的高效募集，证实了多肽疫苗和瘤内注射OK432的协同抗肿瘤作用及其机制。

We had cloned 6 cancer antigen genes and those derived 10 epitope peptides recognized by cytotoxic T-lymphocytes in an HLA-restricted manner were identified. Their expression is not restricted in the lung cancers but also found in other adenocarcinomas and squamous cell carcinomas with relatively high level of expression. Therefore we conducted clinical trials, as the translational research, of the personalized peptide vaccines for patients with various cancers including cancers of the lung, colon, stomach, pancreas, prostate, and malignant brain tumors in total 178 cases using these epitope peptides with previously identified peptides. Local inflammation at the injected sites was frequently observed, however, systemic adverse events have not been detected except for fever(grade 2 of CTCAE ver 3)in some cases. These results indicated the safety of the personalized peptide vaccines. Anti-tumor effects of the vaccines were confirmed in patients with glioblastoma maltiforme. In the case of hormone refractory prostate cancers, combination therapy with the vaccines and low dose estramustin phosphate expressed clinical effects. Since some of the vaccine peptides elicited immediate hypersensitivity-like skin reactions in the prevaccination skin tests, precise mechanisms of the reaction was investigated in animal models. The peptide-induced skin reaction was elicited by degranulation of the mast cells with antibody-independent mechanisms. However, this degranulation of the mast cells was not induced systemic anaphylaxis, because of the rapid degradation of the vaccine peptides in the plasma. This phenomenon was unelated to the anti-cancer effect of the peptide vaccines. We also demonstrated the synergic effect of the peptide vaccination and intratumor injection of OK432 on anti-tumor effect and its mechanism through the efficient recruitment of systemically induced CTLs to the tumor sites.