Identification of new lung cancer antigens and development of peptide vaccine

肺癌新抗原的鉴定及肽疫苗的研制

• 批准号: 15590834
• 负责人: YAMADA Akira
• 金额: $ 2.24万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590834/
• 关键词: Cancer immunotherapy; Cancer antigens; Peptide vaccine; Cancer vaccine; Tumor Immunology; Translational Research; Cytotoxic T lymphocytes; Lung cancer; トランスレーショナルリサーチ; 肺がん; 細胞傷害性T

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.

我们已经克隆了6种癌症抗原基因，并以HLA限制的方式被细胞毒性T淋巴细胞识别出10个表位肽。它们的表达不受肺癌的限制，而是在其他具有相对较高表达水平的腺癌和鳞状细胞癌中发现的。因此，我们针对具有各种癌症的患者进行了个性化肽疫苗，包括肺，结肠癌，胃，胰腺，前列腺，前列腺和恶性脑肿瘤，共178例使用这些表位肽，对各种癌症进行了个性化肽疫苗的临床试验。经常观察到在注射部位处的局部炎症，但是，除了发烧（CTCAE VER 3级2级）外，尚未检测到全身不良事件。这些结果表明个性化肽疫苗的安全性。麦芽胶质细胞瘤患者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，与疫苗和低剂量雌激素磷酸盐的联合疗法表达了临床作用。由于某些疫苗肽在prevacination皮肤测试中引起了直接的高敏性皮肤反应，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用抗体非依赖性机制脱粒而引起的。然而，由于血浆中疫苗肽的迅速降解，肥大细胞的这种脱粒不是诱导的全身性过敏反应。这种现象未与肽疫苗的抗癌作用相关。我们还通过有效募集系统诱导的CTL到肿瘤部位的有效募集，证明了OK432肽疫苗接种和肿瘤内注射对抗肿瘤效应及其机制的协同作用。

项目成果

C型肝炎ウィルス由来ペプチドとインターフェロンとの併用療法

丙型肝炎病毒衍生肽和干扰素的联合治疗

• 发表时间: 2005

Depolmetization of actin Filament by cytochalasin E induces interleukin-8 production and up-regulates CD54 in the Hela epithelial cell line

细胞松弛素 E 对肌动蛋白丝的去极化可诱导 Hela 上皮细胞系中白细胞介素 8 的产生并上调 CD54

• 发表时间: 2003
• 期刊: MIcrobiol Immunol. 47・10
• 作者: Mine T;Sato Y;Noguchi M;Sasatomi T;Gouhara R;Tsuda N;Tanaka S;Shomura H;Katagiri K;Rikimaru T;Shichijo S;Kamura T;Hashimoto T;Shirouze K;Yamada A;Todo S;Itoh K;Yamana H.;N.Tsuda;Koga M;Kawamoto N;Tanaka S;Mine T;Ikewaki N
• 通讯作者: Ikewaki N

Nonmutated Self-Antigen-Derived Cancer Vaccine Peptides Elicit an lgE-Independent but Mast Cell-Dependent Immediate-Type Skin Reaction without Systemic Anaphylaxis.

非突变自身抗原衍生的癌症疫苗肽可引发不依赖于 lgE 但依赖于肥大细胞的立即型皮肤反应，而不会产生全身性过敏反应。

• 发表时间: 2006
• 期刊: J Immunol 176・2
• 作者: Nishio S.;Hatano M.;Nagata M.;Horie S.;Koike T.;Tokuhisa T.;Mochizuki T.;Yamada A
• 通讯作者: Yamada A

Antibody reactive to a hepatitis C virus(HCV)-derived peptide capable of inducing HLA-A2 restricted cytotoxic T lymphocytes is detectable in the majority of HCV-infected individuals without HLA-A2 restriction.

在大多数没有 HLA-A2 限制的 HCV 感染个体中，可检测到与能够诱导 HLA-A2 限制性细胞毒性 T 淋巴细胞的丙型肝炎病毒 (HCV) 衍生肽发生反应的抗体。

• 发表时间: 2004
• 期刊: Microbiol Immunol. 48(7)
• 作者: Takao Y;Yamada A;Yutani S;Sata M;Itoh K.
• 通讯作者: Itoh K.

Antibody reactive to a hepatitis C virus (HCV)-derived peptide capable of inducing HLA-A2 rstricted cytotoxic T lymphocytes is detectable in the majority of HCV-infected individuals without HLA-A2 restriction.

在大多数无 HLA-A2 限制的 HCV 感染个体中，可检测到与丙型肝炎病毒 (HCV) 衍生肽反应的抗体，该肽能够诱导 HLA-A2 限制性细胞毒性 T 淋巴细胞。

• 发表时间: 2004
• 期刊: Microbiol.Immunol. 48
• 作者: H.Shimizu;S.Maruyama;Y.Yuzawa;T.Kato;Y.Miki;Y.Morita;H.Maruyama;K.Egashira;S.Matsuo;Y.Takao
• 通讯作者: Y.Takao