Development of"immunostimulatory virotherapy"to treat various malignancies

开发治疗多种恶性肿瘤的“免疫刺激病毒疗法”

• 批准号: 21390364
• 负责人: YONEMITSU Yoshikazu
• 金额: $ 11.32万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-21390364/
• 关键词: 実験外科学; 樹状細胞; がん免疫; 大量培養; 腹水がん; 胸膜播種; サイトカイン; センダイウイルス

Though DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, its clinical efficacies are still insufficient in many human trials. Especially, malignant ascites(MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers.First, floating cultivation of mononuclear cells from cancer patients under an optimized cytokine cocktail(GM-CSF/SCF) led these cells to stable proliferation and to DC differentiation. As are seen in conventional DCs, expanded DCs showed dendrites after maturation, and endocytotic activities. Expanded DCs also expressed HLA-DR, adhesion molecules, and co-stimulatory molecules and produced inflammatory cytokines as well as conventional DCs did. Functionally, MLR assay revealed that expanded DCs could stimulate allogenic T-cell proliferation to the same extent as conventional DCs.Next, using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A and its decoy receptor, soluble fms-like tryrosine kinase receptor-1(sFLT-1), was a major cause of MA resistance to DC-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene. deleted recombinant Sendai virus(rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors.

尽管基于dc的癌症免疫疗法已被认为是多种恶性肿瘤的潜在治疗方法，但在许多人体试验中，其临床疗效仍然不足。特别是，恶性腹水（MA）是一种高度难治性和免疫治疗抵抗状态的晚期胃肠道和卵巢癌。首先，将来自癌症患者的单核细胞在优化的细胞因子混合物（GM-CSF/SCF）下进行漂浮培养，使这些细胞稳定增殖并向DC分化。与常规树突细胞一样，扩大后的树突细胞成熟后出现树突，并具有内吞活性。与常规dc一样，扩增dc也表达HLA-DR、粘附分子和共刺激分子，并产生炎症细胞因子。在功能上，MLR分析显示扩增的dc可以刺激同种异体t细胞的增殖，其程度与常规dc相同。接下来，使用CT26结肠癌细胞的小鼠MA模型，我们在这里确定VEGF-A与其诱饵受体（可溶性fms样tryrosine kinase receptor-1， sFLT-1）之间的不平衡是MA对基于dc的免疫治疗产生耐药性的主要原因。我们发现VEGF-A/sFLT-1的比值不仅在小鼠中升高，而且在人MA和f基因中也升高。缺失的重组仙台病毒（rSeV/dF）介导的dc分泌人sFLT-1不仅增强了dc本身的活性，而且还显著提高了荷瘤动物的存活率，这与CTL活性增强及其对腹膜肿瘤的浸润有关。

项目成果

Urokinase-targeted cell-cell fusion by oncolytic Sendai virus eradicates orthotropic model of glioblastomas by a pronounced synergy with interferon-β.

溶瘤仙台病毒的尿激酶靶向细胞间融合通过与干扰素-β的显着协同作用消除了胶质母细胞瘤的正交各向异性模型。

• 发表时间: 2010
• 期刊: Molecular Therapy
• 影响因子: 12.4
• 作者: Hasegawa Y;et al
• 通讯作者: et al

Inflammation and Aging : Inflammatory cascade during atherogenesis : role of intraplaque angiogenesis and lymphangiogenesis

炎症与衰老：动脉粥样硬化形成过程中的炎症级联反应：斑块内血管生成和淋巴管生成的作用

• 发表时间: 2011
• 作者: Suzuki H;Onishi H;Wada J;Yamasaki A;Tanaka H;Nakano K;Morisaki T;Yoshikazu Yonemitsu
• 通讯作者: Yoshikazu Yonemitsu

Advanced Lecture : BioKnife : the state-of-art for the new era of oncolytic therapy

高级讲座：生物刀：溶瘤治疗新时代的最先进技术

• 发表时间: 2010
• 作者: Tsutsui M;Iizuka N;Moribe T;Miura T;Kimura N;Tamatsukuri S;Ishitsuka H;Fujita Y;Hamamoto Y;Tsunedomi R;Iida M;Tokuhisa Y;Sakamoto K;Tamesa T;Sakaida I;Oka M;Yoshikazu Yonemitsu
• 通讯作者: Yoshikazu Yonemitsu

Pharma Medica特集:神経芽腫「センダイウイルスベクター導入樹状細胞を用いた神経芽腫の免疫治療」

Pharma Medica 专题：神经母细胞瘤“使用仙台病毒载体转导的树突状细胞对神经母细胞瘤进行免疫治疗”

• 发表时间: 2011
• 作者: 田尻達郎;他
• 通讯作者: 他

分子細胞治療フロンティア

分子细胞治疗前沿

• 发表时间: 2010
• 作者: 吉田久美;他
• 通讯作者: 他