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.

新辅助原位细胞毒性基因治疗可能会引发全身免疫反应，从而影响隐匿性微转移性疾病。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）基因加更昔洛韦（GCV）治疗作为新辅助前列腺内注射治疗局部高危前列腺癌。本研究评估基因治疗后的全身 T 细胞反应。我们在这项 I.II 期试验中招募了 5 名患有临床局限性前列腺癌但复发风险较高（Kattan 列线图评分> 115）的男性。前列腺内病毒注射（两次）后进行 2 周的 GCV，4 周后进行前列腺切除术。所有患者在载体注射和 GCV 治疗后立即观察到血清 PSA 降低。平均减少量为 31.1%，范围为 24.8% 至 38.9%。治疗前 HLA-DR 激活标记阳性的 CD8+T 细胞平均百分比为 10.6%。治疗后第2天、第7天、第14天、第16天和第56天，CD8+DR+T细胞的平均百分比增加了14.0%、12.3%、19.7%、25.4%和14.9%，具有统计学意义（第 14 天；p=0.0431，第 16 天；p=0.0431)。临床试验条件下 HSV-tk+GCV 基因治疗后的 T 细胞反应。注射载体后，外周血中活化的 CD8+T 细胞有所增加，表明在这种新辅助治疗环境中细胞介导的免疫反应成分有可能被激活。

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

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

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

Single Infusion of Zoledronic Acid to Prevent Androgen Deprivation Therapy-induced Bone Loss in Men With Hormone-naive Prostate Carcinoma

• DOI: 10.1002/cncr.24404
• 发表时间: 2009-08-01
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Satoh, Takefumi;Kimura, Masaki;Baba, Shiro
• 通讯作者: Baba, Shiro

ハイリスク前立腺癌に対するネオアジュバントHSV-tk遺伝子治療の検討

高危前列腺癌新辅助 HSV-tk 基因治疗的考虑

• 发表时间: 2011
• 作者: 佐藤威文;久保誠;田畑健一;黒坂眞二;柳澤信之;松本和将;藤田哲夫;佐藤絵里奈;伊東一郎;小幡文弥;三枝信;岡安勲;那須保友;公文裕巳;馬場志郎
• 通讯作者: 馬場志郎