Identification of new lung cancer antigens and development of peptide vaccine

我们克隆了6个肿瘤抗原基因，并鉴定了10个表位肽，这些表位肽被细胞毒性t淋巴细胞以hla限制性方式识别。它们的表达不仅局限于肺癌，在其他腺癌和鳞状细胞癌中也有较高的表达水平。因此，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肽疫苗的临床试验，作为转化研究，总共178例患者使用这些表位肽和先前鉴定的肽。注射部位的局部炎症经常被观察到，然而，除了发烧（CTCAE 3级2级）外，未发现全身不良事件。这些结果表明了个性化肽疫苗的安全性。在多形性胶质母细胞瘤患者中证实了疫苗的抗肿瘤作用。在激素难治性前列腺癌的病例中，联合疫苗和低剂量磷酸雌二醇表达了临床效果。由于在疫苗接种前的皮肤试验中，一些疫苗肽引起了立即的过敏样皮肤反应，因此在动物模型中研究了这种反应的确切机制。肽诱导的皮肤反应是由肥大细胞脱颗粒引起的，其机制与抗体无关。然而，由于血浆中疫苗肽的快速降解，这种肥大细胞的脱颗粒不会引起全身性过敏反应。这种现象与肽疫苗的抗癌作用无关。我们还证明了多肽疫苗接种和肿瘤内注射OK432对抗肿瘤作用的协同作用及其机制，通过系统诱导的ctl有效募集到肿瘤部位。

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.