Neoadjuvant in situ gene therapy with adenoviral delivery of HSV-tK gene for patients with high-risk prostate cancer

采用腺病毒递送 HSV-tK 基因的新辅助原位基因疗法治疗高危前列腺癌患者

• 批准号: 21592060
• 负责人: SATOH Takefumi
• 金额: $ 2.83万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21592060/
• 关键词: 前立腺癌; 遺伝子治療; ネオアジュバント; ハイリスク群; アデノウィルスベクター

Neoadjuvant in situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult micro-metastatic disease. We are currently conducting adenoviral vector mediated Herpes Simplex Virus-thymidine kinese(HSV-tk) gene plus ganciclovir(GCV) therapy as neoadjuvant intraprostatic injection for localized high-risk prostate cancer. This study evaluates the systemic T-cell response following gene therapy.We enrolled 5 men with clinically localized prostate cancer but high risk for recurrence(Kattan nomogram score> 115) in this Phase I. II trial. Intraprostatic viral injections(two) were followed by 2 weeks of GCV and prostatectomy 4 weeks later.A reduction in serum PSA was observed immediately after vector injection and GCV therapy in all patients. The mean reduction was 31.1% and ranged from 24.8 to 38.9%.The pretreatment mean percentage of CD8+T cells positive for the HLA-DR marker of activation was 10.6%. For day 2, day 7, day 14, day 16 and day 56 post treatment, the mean percent of CD8+DR+T cells increased by 14.0%, 12.3%, 19.7%, 25.4% and 14.9%, which were statistically significant(day 14 ; p=0.0431, day 16 ; p=0.0431).We present evidence of systemic T-cell responses following HSV-tk+GCV gene therapy under clinical trial condition. There was an increase in activated CD8+T cells in the peripheral blood following vector injection suggesting the potential for activation of components of cell-mediated immune response in this neoadjuvant setting.

新辅助原位细胞毒基因治疗可潜在地触发全身免疫反应，从而可能影响隐匿性微转移疾病。我们目前正在进行腺病毒载体介导的单纯疱疹病毒胸苷激酶(HSV-tk)基因联合更昔洛韦(GCV)治疗局限性高危前列腺癌的新辅助前列腺癌治疗。这项研究评估了基因治疗后的全身T细胞反应。在这项I、II期试验中，我们招募了5名临床上有局限性前列腺癌但复发风险高的男性患者(Kitan Norgraph Score&gt；115)。前列腺腔内注射病毒2周后行GCV治疗，4周后行前列腺切除术。所有患者在注射载体和GCV治疗后血清PSA立即降低。平均下降31.1%，降幅在24.8%~38.9%之间。治疗前CD8+T细胞的平均阳性百分率为10.6%。在治疗后第2天、第7天、第14天、第16天和第56天，CD8+DR+T细胞的平均百分比分别增加了14.0%、12.3%、19.7%、25.4%和14.9%，差异有统计学意义(第14天；p=0.0431；第16天；p=0.0431)。在载体注射后，外周血中激活的CD8+T细胞增加，这表明在这种新的佐剂环境中，细胞介导的免疫反应的组成部分可能被激活。

项目成果

講演5:前立腺がんの転移・再発治療

第五讲：前列腺癌转移和复发的治疗

• 发表时间: 2011
• 作者: Nakagawa H;Niu K;Hozawa A;Kaiho Y;Ikeda Y;Imanishi R;Miyazato M;Nagatomi R;Tsuji I;Arai Y;佐藤威文
• 通讯作者: 佐藤威文

Neoadjuvant In Situ Gene Therapy for Prostate Cancer : Kitasato Trial

前列腺癌新辅助原位基因治疗：Kitasato 试验

• 发表时间: 2010
• 作者: 佐藤威文;久保誠;柳澤信之;田畑健一;松本和将;佐藤絵里奈;大草洋;岩村正嗣;小幡文弥;岡安勲;那須保友;公文裕巳;馬場志郎
• 通讯作者: 馬場志郎

Systemic T-cell activation following neoadjuvant in situ gene therapy in high-risk prostate cancer patients

高危前列腺癌患者新辅助原位基因治疗后的全身 T 细胞激活

• 作者: 松本和将;松本俊英;入江啓;藤田哲夫;佐藤威文;佐藤雄一;岩村正嗣;Takefumi Satoh,Makoto Kubo,Ken-ichi Tabata,Shinji Kurosaka,Kazumasa Matsumoto,Tetsuo Fujita Fumiya Obata,Yasutomo Nasu,Hiromi Kumon,Dov Kadmon,Malcolm K Brenner,Timothy C Thompson,Shiro Baba
• 通讯作者: Takefumi Satoh,Makoto Kubo,Ken-ichi Tabata,Shinji Kurosaka,Kazumasa Matsumoto,Tetsuo Fujita Fumiya Obata,Yasutomo Nasu,Hiromi Kumon,Dov Kadmon,Malcolm K Brenner,Timothy C Thompson,Shiro Baba

L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer

• DOI: 10.1111/j.1440-1827.2008.02319.x
• 发表时间: 2009-01-01
• 期刊: PATHOLOGY INTERNATIONAL
• 影响因子: 2.2
• 作者: Sakata, Takeshi;Ferdous, Golam;Okayasu, Isao
• 通讯作者: Okayasu, Isao

A phase I study of personalized peptide vaccination for advanced urothelial carcinoma patients who failed treatment with methotrexate, vinblastine, adriamycin and cisplatin

• DOI: 10.1111/j.1464-410x.2010.09933.x
• 发表时间: 2011-09-01
• 期刊: BJU INTERNATIONAL
• 影响因子: 4.5
• 作者: Matsumoto, Kazumasa;Noguchi, Masanori;Itoh, Kyogo
• 通讯作者: Itoh, Kyogo