作者: Noda, Takuo ; Tanimoto, Terutaka ; Kagawa, Shunsuke ; Tazawa, Hiroshi ; Watanabe, Hinako ; Urata, Yasuo ; Kuroda, Shinji ; Tani, Morimichi ; Nouso, Hiroshi ; Oyama, Takanori ; Fujiwara, Toshiyoshi

BACKGROUND/AIM:

Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. Although immunotherapy with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) has emerged as novel antitumor therapy, high-risk NB tumors are refractory to ICI therapy. Oncolytic virotherapy is expected to potentiate the antitumor immune response by inducing immunogenic cell death (ICD). In the present study, we assessed the therapeutic potential of OBP-301 and OBP-702, telomerase-specific oncolytic adenoviruses, for the induction of ICD and combined effect with PD-1 blockade against NB cells.

MATERIALS AND METHODS:

The cytopathic activity of OBP-301 and OBP-702 was assessed using three human MYCN-amplified NB cell lines (IMR-32, LA-N-5, and NB-1) and a murine non-MYCN-amplified NB cell line (Neuro-2a). Virus-mediated antitumor effect was assessed by analyzing cell viability, secretion of extracellular adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1), apoptosis, autophagy, and PD-L1 levels. A subcutaneous Neuro-2a tumor model was used to evaluate the in vivo antitumor effect of combination therapy with OBP-702 and anti-PD-1 antibody.

RESULTS:

OBP-702 exhibited stronger cytopathic activity, inducing ICD with secretion of ATP and HMGB1, compared to OBP-301 in human and murine NB cells. OBP-301 and OBP-702 increased apoptosis, autophagy, and PD-L1 expression in murine NB cells. Moreover, OBP-702 significantly prolonged the survival of tumor-bearing mice compared to monotherapy with PD-1 blockade.

CONCLUSION:

OBP-702 is a promising antitumor strategy to promote the antitumor effect of ICIs by inducing ICD against NB tumors.

2026-02-01·CANCER GENE THERAPY

p53-armed oncolytic adenovirus induces apoptosis in pancreatic cancer-associated stellate cells via macropinocytosis

Article

作者: Urata, Yasuo ; Kano, Mitsunobu R ; Kagawa, Shunsuke ; Tanaka, Hiroyoshi Y ; Yoshida, Ryuichi ; Kuroda, Shinji ; Nishiyama, Takeyoshi ; Shoji, Ryohei ; Kikuchi, Satoru ; Takahashi, Yosuke ; Masamune, Atsushi ; Noma, Kazuhiro ; Umeda, Yuzo ; Nagai, Yasuo ; Tazawa, Hiroshi ; Ohara, Toshiaki ; Hashimoto, Naoyuki ; Fujiwara, Toshiyoshi ; Kajiwara, Yoshinori

Abstract:

Pancreatic ductal adenocarcinoma (PDAC)-associated pancreatic stellate cells (PSCs) promote PDAC tumor progression. Notably, PDAC tumors display enhanced macropinocytosis, resulting in enhanced uptake of extracellular particles, including nutrients and viruses. We previously demonstrated the therapeutic potential of telomerase-specific oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against human PDAC cells. However, it remains unclear whether macropinocytosis promotes the virus sensitivity of PDAC-associated PSCs. Here, we show that PSCs activated by human PDAC cells (Panc-1 and BxPC-3) exhibit enhanced sensitivity to wild-type and oncolytic adenoviruses via enhanced macropinocytosis. The virus sensitivity of PSCs was analyzed for the infectivity, replication, and cytopathic activity of wild-type and oncolytic adenoviruses. PDAC-associated PSCs were more sensitive to wild-type and oncolytic adenoviruses than were control PSCs; this sensitivity was mediated by activation of macropinocytosis. In three-dimensional (3D) culture models, p53-armed OBP-702 decreased the viability of PDAC-associated PSCs more strongly than did non-armed OBP-301, reflecting induction of p53-mediated apoptosis. Co-inoculation of PSCs enhanced the growth of PDAC tumors, an effect that was attenuated by OBP-702-mediated p53 activation in the tumor stroma. Our results suggest that p53-armed oncolytic adenovirus OBP-702 eliminates PDAC-associated PSCs via enhancement of macropinocytosis-mediated virus entry and induction of p53-mediated apoptosis.

2026-01-01·ANTICANCER RESEARCH

P53-Armed Oncolytic Virotherapy Promotes the Efficacy of PD1 Blockade in Murine Osteosarcoma Tumors

Article

作者: Ozaki, Toshifumi ; Kure, Miho ; Kagawa, Shunsuke ; Yoshida, Aki ; Urata, Yasuo ; Mochizuki, Yusuke ; Demiya, Koji ; Kunisada, Toshiyuki ; Komatsubara, Tadashi ; Fujiwara, Tomohiro ; Hasei, Joe ; Tazawa, Hiroshi ; Kondo, Hiroya ; Fujiwara, Toshiyoshi ; Uotani, Koji

BACKGROUND/AIM:

Osteosarcoma (OS) is refractory to immune checkpoint inhibitors targeting programmed cell death 1 (PD1)/PD ligand 1 (PD-L1) due to poor immune response. We previously developed telomerase-specific, replication-competent oncolytic adenoviruses non-armed OBP-301 and P53-armed OBP-702 that exert antitumor efficacy against human OS cells. Recently, we demonstrated that P53-armed OBP-702 induces more profound immunogenic cell death and antitumor immune response against human and murine OS cells than does non-armed OBP-301. In the present study, we assessed the combined efficacy of PD1 blockade and P53-armed OBP-702 against murine OS cells.

MATERIALS AND METHODS:

Three murine OS cell lines (K7M2, NHOS, NHOS-LM4) were used to assess the cytopathic effect of non-armed OBP-301 and P53-armed OBP-702 by XTT assay. Virus-induced immunogenic cell death was assessed by analyzing the levels of extracellular adenosine triphosphate and high-mobility group box protein B1. The expression of PD-L1 and PD-L2 was analyzed by flow cytometry. The malignant potential of NHOS-LM4 cells was analyzed by a migration and invasion assay. An orthotopic NHOS-LM4 tumor model was used to evaluate the antitumor efficacy of combination therapy with P53-armed OBP-702 and anti-PD1.

RESULTS:

P53-armed OBP-702 exhibited antitumor potential for the induction of immunogenic cell death, apoptosis, autophagy, and PD-L1/2 upregulation in K7M2 and NHOS cells. NHOS-LM4 cells showed increased migratory and invasive ability compared to NHOS cells. P53-armed OBP-702 significantly suppressed the malignant potential of NHOS-LM4 cells. Combination dosing showed that P53-armed OBP-702 significantly promoted the antitumor effect of PD1 blockade against NHOS-LM4 tumors.

CONCLUSION:

Our results suggest that P53-armed OBP-702 is a promising agent for improving the antitumor effect of PD1 blockade in treating invasive OS.

项与 Pfifteloxin 相关的新闻（医药）

2025-10-29

·真卓未徕医疗观察

日本科研团队多路出击，挑战“癌中之王”胰腺癌治疗新策略

胰腺癌五年生存率不足10%的魔咒，正被日本科学家们用病毒、疫苗和AI等新手段逐一打破。胰腺癌因其发病隐匿、恶性程度高、预后极差，被称为“癌中之王”。日本厚生劳动省的人口动态统计显示，日本胰腺癌死亡人数每年约4万人，是继肺癌、大肠癌之后死亡人数第三多的癌症，5年生存率仅8.5%，在所有癌症中最低。传统的化疗方案效果有限，科学家们正积极探索新的治疗策略。 01 病毒疗法：从麻疹到精准癌细胞杀手冈山大学研究团队正在准备一种癌症治疗用病毒制剂OBP-702的第Ⅰ期临床试验。这种新型病毒制剂是在第一代癌病毒制剂Telomelysin（OBP-301）基础上改良而成的第二代产品。研究人员在黑田新士讲师的带领下，已经通过动物实验证实，OBP-702对缺乏治疗效果的胰腺癌也能发挥治疗效果。该试验计划在冈山大学医院、爱媛大学医学部附属医院和国立癌症研究中心研究所三个设施中进行，主要针对标准治疗无效的胰腺癌患者。 02 新机制探索：蛋白质控制与药物敏感性京都大学研究团队今年7月阐明了高恶性胰腺癌的部分分子机制，发现“波形蛋白”的表达与抗癌药物敏感性及癌症转移相关。研究团队发现，当PBRM1功能低下时，波形蛋白表达更为活跃。供图：京都大学在向小鼠投用抑制波形蛋白功能的药物后，癌细胞转移得到了有效抑制。值得关注的是，这种波形蛋白抑制剂已作为治疗脂质异常症的药物获得审批。研究的主导者福田晃久副教授表示：“抑制胰腺癌的转移至关重要。希望在1年内启动由医生主导的临床试验”。 03 AI助力：两天筛选出新药靶点日本FRONTEO公司利用AI药物研发辅助服务“DDAIF”，在短短两天内从约2万个人类全基因中成功提取出17个胰腺癌药物研发靶点。在这17个靶向分子候选基因中，实验确认有6个能够抑制胰腺癌细胞的增殖。研究概要图 (供图：FRONTEO) 其中4个基因尚未有论文报道其与胰腺癌的关联性，另外2个基因仅有一篇论文报道，具有极高的新颖性。传统药物研发方法中，“靶向探索”过程往往需要两年以上时间，而AI技术将其缩短到了两天。 04 细菌疗法：利用微生物攻击癌细胞北陆先端科学技术大学院大学与第一三共株式会社开发出利用两种细菌攻击癌细胞的方法，并通过小鼠实验证实了其抗癌效果。该方法利用了自然环境中存在的光合细菌“沼泽红假单胞菌”以及癌症常驻细菌“奇异变形杆菌”。这两种细菌都具有在癌细胞活跃的场所——低氧环境中增殖的特性。北陆先端大学等宣布开发出利用兩种细菌破坏癌细胞的方法（8月4日，東京千代田）研究团队在实验中将人的大肠癌、卵巢癌、胰腺癌三种癌细胞分别移植到免疫机能失效的小鼠体内，然后向小鼠尾部注射这两种细菌。数日后，三种癌症细胞几乎全部消失。 05 化疗方案比较：确立标准治疗基础日本研究者Ohba等进行的GENERATE试验是一项在日本45个中心开展的随机、开放标签的Ⅱ/Ⅲ期临床试验，直接比较了三种治疗方案对转移性或复发性胰腺癌的疗效。该研究将患者随机分为三组，分别接受mFOLFIRINOX方案、S-IROX方案和白蛋白结合型紫杉醇联合吉西他滨方案。结果显示，白蛋白结合型紫杉醇联合吉西他滨组的中位总生存期更新为17.0个月，而mFOLFIRINOX组为14.0个月，S-IROX组为13.6个月。在安全性方面，3至4级不良事件中，白细胞减少在白蛋白结合型紫杉醇联合吉西他滨组更为常见（60.3%），而厌食和腹泻在mFOLFIRINOX组和S-IROX组更为频繁。研究结论是，在转移性或复发性胰腺癌的一线治疗中，白蛋白结合型紫杉醇联合吉西他滨是更合适的选择。胰腺癌治疗研究正在跨越传统的化疗和放疗边界。从病毒制剂、细菌疗法到AI驱动的药物发现，日本科研团队的努力预示着未来胰腺癌治疗格局可能迎来重大变革。东京科学大学村田昌之特任教授评价AI在药物发现中的应用时表示：“在极短时间内发现论文未报告的创药靶标且锁定多个靶向候选物，这是一项传统方法无法想象的创新技术”。这些努力共同构成了胰腺癌治疗研究的希望图景，为攻克“癌中之王”带来了新的曙光。参考文献： [1]Journal of Clinical InvestigationPolybromo 1/vimentin axis dictates tumor grade, epithelia-mesenchymal transition, and metastasis in pancreatic cancerDOI：doi.org/10.1172/JCI177533 [2]Nature Biomedical EngineeringTumour-resident oncolytic bacteria trigger potent anticancer effects through selective intratumoural thrombosis and necrosisDOI:10.1038/s41551-025-01459-9 END 健康管理财富传承全球通途

临床1期疫苗微生物疗法

100 项与 Pfifteloxin 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
结直肠癌	临床前	日本	Medical School Okayama University	2025-04-28
结肠癌	临床前	日本	Oncolys BioPharma, Inc.	2024-04-08
结肠癌	临床前	日本	Okayama University	2024-04-08
胰腺癌	临床前	日本	Okayama University	2024-04-08
胰腺癌	临床前	日本	Oncolys BioPharma, Inc.	2024-04-08