Development of the therapy with an intratumoral administration of dendritic cells in combination with radiation or anti-cancer drugs against oral cancer : Application to clinical trial.

树突状细胞瘤内给药联合放射或抗癌药物治疗口腔癌的疗法的开发：应用于临床试验。

• 批准号: 16592006
• 负责人: YOSHIDA Hideo
• 金额: $ 2.3万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16592006/
• 关键词: Cancer Immunotherapy; dendritic cell; OK-432; TS-1; Toll-loke receptor; lipoteichoic acid-related molecule OK-PSA; clinical trial; 細胞免疫療法; OK-432; Toll-like receptor 4 (TLR4)

Dendritic cells (DCs) are professional antigen-presenting cells. Adequately matured DCs can stimulate T cells to induce tumor-specific cytotoxic T lymphocytes (CTLs). A streptococcal anticancer immunotherapeutic agent OK-432 can strongly mature DCs. In tumor-bearing mouse model, radiation therapy (RT) or oral administration of anticancer drug TS-1 followed by an intratumoral injection of syngeneic bone-marrow-derived DCs and of OK-432 resulted in inducing CTLs and in inhibiting tumor growth. The therapy did not elicit any significant effects in tumor-bearing mice in which Toll-like receptor (TLR) 4 is mutated. We have already succeeded in isolating an active component of OK-432 (lipoteichoic acid-related molecule OK-PSA). OK-PSA matured DCs far better, than original OK-432 in vitro, and OK-PSA-treated DCs stimulated allogeneic T cells to produce IFN-γ, and to induce allo-antigen specific CTLs. In in vivo model, TS-1+DCs+OK-PSA therapy exhibited anticancer effect stronger than the therapy using TS-1, DCs and OK-432. Based on these basic data, we have started an early stage clinical trial, "the therapy with an intratumoral administration of DCs in combination with TS-1 and OK-432", in oral cancer patients in which the standard therapies were not effective. Of 5 cases, complete remission (CR) was observed in one case, partial remission (PR) in 3 cases, and stable desease (SD) in one case. No significant toxicity over grade 3 was observed. It was strongly suggested that an intratumoral administration in combination with TS-1 and OK-432 is safety and effective in oral cancer patients.

树突状细胞（Dendritic cells，DC）是专职的抗原提呈细胞。成熟的DC可以刺激T细胞诱导肿瘤特异性细胞毒性T淋巴细胞（CTL）。链球菌抗肿瘤免疫抑制剂OK-432可使DC强烈成熟。在荷瘤小鼠模型中，放射治疗（RT）或口服抗癌药物TS-1，然后瘤内注射同基因骨髓来源的DC和OK-432导致诱导CTL和抑制肿瘤生长。这种疗法在Toll样受体（TLR）4突变的荷瘤小鼠中没有引起任何显著的效果。我们已经成功分离出OK-432（脂磷壁酸相关分子OK-PSA）的活性成分。OK-PSA处理的DC在体外的成熟度远高于原始OK-432，并且OK-PSA处理的DC刺激同种异体T细胞产生IFN-γ，并诱导同种异体抗原特异性CTL。在体内模型中，TS-1+DCs+OK-PSA治疗显示出比使用TS-1、DCs和OK-432的治疗更强的抗癌效果。基于这些基础数据，我们已经开始了早期临床试验，“肿瘤内施用DC与TS-1和OK-432组合的治疗”，在标准治疗无效的口腔癌患者中。5例中完全缓解（CR）1例，部分缓解（PR）3例，稳定（SD）1例。未观察到超过3级的显著毒性。强烈提示肿瘤内施用与TS-1和OK-432组合在口腔癌患者中是安全和有效的。

项目成果

Induction of apoptosis in human head and neck cancer cell lines by an active component of OK-432 through p53-independent pathway via Toll-like receptor (TLR) 4 signaling.

OK-432 的活性成分通过 Toll 样受体 (TLR) 4 信号传导通过 p53 独立途径诱导人头颈癌细胞系凋亡。

• 发表时间: 2005
• 期刊: Jpn J Cancer Chemother 31(11)
• 作者: 鈴木恵子;山崎安晴;瀬崎晃一郎;内沼栄樹;Koji Harada;Masaru Murata;Yamazaki Y;Tomiyuki Tano
• 通讯作者: Tomiyuki Tano

Intratumoral administration of dendritic cells in combination with TS-1, an oral fluoropyrimidine anti-cancer drug, and OK-432, a streptococcal agent.

树突状细胞与 TS-1（一种口服氟嘧啶抗癌药物）和 OK-432（一种链球菌药物）联合进行瘤内给药。

• 发表时间: 2004
• 期刊: J Jpn Stomatol Soc 53(1)
• 作者: Tetsuya Kawakita;Shinichi Takahashi;et al.;Yoshiki Ryoma;小俣裕昭 他2名;Masato Okamoto
• 通讯作者: Masato Okamoto

Anti-cancer effect of an intratumoral injection of dendritic cells expressing TLR4 in combination with an active component of OK-432 in TLR4-deficient mice.

在 TLR4 缺陷小鼠中瘤内注射表达 TLR4 的树突状细胞与 OK-432 活性成分的抗癌作用。

• 发表时间: 2004
• 期刊: Jpn J Cancer Chemother 31(11)
• 作者: S.OKA;C.Richard CHAPMAN;B.KIM;I.NAKAJIMA;O.SHIMIZU;Y.OI;Kazuhiro Hasegawa;Sharif Uddin Ahmed;茂木勝美;Hiroaki Omata;Masato Okamoto;Masato Okamoto;Hiroaki Omata;Tomiyuki Tano;Ammar Almofti;Hiroaki Omata;Masato Okamoto;Tetsuya Oshimawa
• 通讯作者: Tetsuya Oshimawa

Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamour cell carcinoma

通过人口腔鳞状细胞癌中 CXCR4 的过表达获得淋巴结，但不获得远处转移潜能

• 发表时间: 2004
• 期刊: Lab Invest 84・12
• 作者: T.Wakira;M.Mogi;K.Kurita;M.Kuzushima;A.Togari;Masato Okamoto;小俣裕昭 他4名;押川哲也;Hiroyuki Nakagawa;Wakita et al.;小俣裕昭 他4名;Koji Harada;Sharif Uddin Ahmed;田野智之;Koji Harada;Hiroaki Omata;両馬良樹;Hiroaki Omata;Koji Harada;Hiroaki Omata;Masato Okamoto;Supriatno;Sharif Uddin Ahmed;Masato Okamoto;Daisuke Uchida;Masato Okamoto;Daisuke Uchida
• 通讯作者: Daisuke Uchida

Expression of muscle-specific transcription factor MyoD in himan salivary duct cells.

肌肉特异性转录因子 MyoD 在希曼唾液管细胞中的表达。

• 发表时间: 2004
• 期刊: Jpn J Tissue Cult Dent Res 13(1)
• 作者: Fukuda A.;Morita S.;Masato Okamoto;木下 篤敬;Yoshiki Ryoma;木下篤敬 他;Yoshiki Ryoma;Tetsuya Tamatani;Atsutaka Kinoshita;Takashi Bando
• 通讯作者: Takashi Bando