Identification of new lung cancer antigens and development of peptide vaccine

我们已经克隆了6个癌抗原基因，并鉴定了这些基因衍生的10个表位肽，这些表位肽以HLA限制性方式被细胞毒性T淋巴细胞识别。它们的表达不仅限于肺癌，而且在其他腺癌和鳞状细胞癌中也有相对高水平的表达。因此，我们使用这些表位肽和先前鉴定的肽，在总共178个病例中进行了用于患有各种癌症（包括肺癌、结肠癌、胃癌、胰腺癌、前列腺癌和恶性脑肿瘤）的患者的个性化肽疫苗的临床试验，作为转化研究。经常观察到注射部位的局部炎症，然而，除了在某些病例中的发热（CTCAE版本3的2级）外，未检测到全身不良事件。这些结果表明了个体化肽疫苗的安全性。在恶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情况下，疫苗和低剂量磷酸雌莫司汀的联合治疗表现出临床效果。由于一些疫苗肽在接种前皮肤试验中引起了立即的过敏样皮肤反应，因此在动物模型中研究了反应的精确机制。肽诱导的皮肤反应是通过肥大细胞的脱颗粒引起的，具有抗体非依赖性机制。然而，由于疫苗肽在血浆中的快速降解，肥大细胞的这种脱粒不会诱导全身过敏反应。这种现象与肽疫苗的抗癌作用无关。我们还证实了肽疫苗接种和瘤内注射OK432对抗肿瘤效应的协同作用及其通过有效地将全身诱导的CTL募集到肿瘤部位的机制。

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.