A Phase 1 Study to Evaluate the Safety, Tolerability, Immunogenicity and Anti-Tumour Activity of BIL06v/Alhydrogel in Patients with Advanced Solid Tumours

开始日期2018-08-15

申办/合作机构

Biosceptre (Aust) Pty Ltd.

NCT02587819 / Completed临床1期

An Open-Label Phase 1 Investigation of the Safety and Tolerability of BSCT (Anti-nf-P2X7) 10% Ointment When Applied Twice Daily for 28 Days in Male and Female Patients With Basal Cell Carcinoma

This is a Phase 1, open-label, single-arm, multicenter study to assess the safety and tolerability of BSCT (anti-nf-P2X7) 10% Ointment in subjects with BCC.

开始日期2013-05-01

申办/合作机构

Biosceptre (Aust) Pty Ltd.

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100 项与 nfP2X7 相关的临床结果

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100 项与 nfP2X7 相关的转化医学

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0 项与 nfP2X7 相关的专利（医药）

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项与 nfP2X7 相关的文献（医药）

2024-01-01·Clinical & Translational Immunology

Engineered CAR‐T cells targeting the non‐functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer

Article

作者: Bandara, Veronika ; Foeng, Jade ; Sadlon, Timothy J ; Macpherson, Anne M ; Oehler, Martin K ; Ricciardelli, Carmela ; McColl, Shaun R ; Willett, Vasiliki J ; Gundsambuu, Batjargal ; Coombs, Justin ; Niktaras, Victoria M ; Napoli, Silvana ; Barry, Simon C ; Chapman, Hayley ; Lokman, Noor A

AbstractObjectivesRecent studies have identified expression of the non‐functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour‐associated antigen candidate for chimeric antigen receptor (CAR)‐T‐cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7‐CAR‐T cells on ovarian cancer using in vitro and in vivo models.MethodsWe evaluated the effects of nfP2X7‐CAR‐T cells on ovarian cancer cell lines (SKOV‐3, OVCAR3, OVCAR5), normal peritoneal cells (LP‐9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7‐CAR‐T cells on patient‐derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7‐CAR‐T cells in vivo using the OVCAR‐3 xenograft model in NOD‐scid IL2Rγnull (NSG) mice.ResultsOur study found that nfP2X7‐CAR‐T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un‐transduced CD3+ T cells in vitro. However, no significant effects of nfP2X7‐CAR‐T cells were observed for SKOV3 or normal peritoneal cells (LP‐9) cells with low P2X7 receptor expression. Treatment with nfP2X7‐CAR‐T cells increased apoptosis compared with un‐transduced T cells in patient‐derived explants and correlated with CD3 positivity. Treatment with nfP2X7‐CAR‐T cells significantly reduced OVCAR3 tumour burden in mice compared with un‐transduced CD3 cells for 7–8 weeks.ConclusionThis study demonstrates that nfP2X7‐CAR‐T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.

2019-01-01·Oncogene1区 · 医学

ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival

1区 · 医学

Article

作者: Oliphant, C J ; Peille, A L ; Di Virgilio, F ; Bronsert, P ; Hassan, S ; Lara, R ; McNulty, S ; Gilbert, S M ; Falzoni, S

The ATP-gated receptor P2X₇ is expressed in multiple malignant tumours including neuroblastoma, melanoma, prostate, lung and breast. P2X₇ has a significant role in mediating diverse cell responses, which upon dysregulation are associated with tumour initiation and development. The rapid, ATP-mediated activation of P2X₇ induces a fast-inward cation current in cells. However, prolonged ATP-mediated activation of P2X₇ leads to formation of a pore that increases membrane permeability and eventually causes cell death. This presents a potential paradox, as the tumour microenvironment contains extracellular ATP at levels sufficient to activate the P2X₇ pore and trigger cell death. However, P2X₇ expression is associated with enhanced cancer cell survival, proliferation and metastatic potential. At least one distinct conformational form of P2X₇, termed non-pore functional P2X₇ (nfP2X₇), has been described, which is not able to form a functional pore. We demonstrate for the first time in this study that exposure to a high ATP concentration, equivalent to those measured in the tumour microenvironment, drives nfP2X₇ expression and also that nfP2X₇ is essential for tumour cell survival. We show that monoclonal antibodies raised against a P2X₇ amino acid sequence (200-216), whose conformation is distinct from that of wild-type (WT) P2X₇, bind specifically to nfP2X₇ expressed on the surface of tumour cells. We also show that nfP2X₇ is broadly expressed in patient-derived tumour sections from a wide range of cancers. Therefore, antibodies raised against E200 provide tools that can differentiate between forms of the P2X₇ receptor that have a key role in cancer.

2002-03-01·Arteriosclerosis, Thrombosis, and Vascular Biology1区 · 医学

Purinergic Signaling and Vascular Cell Proliferation and Death

1区 · 医学

Review

作者: Burnstock, Geoffrey

项与 nfP2X7 相关的新闻（医药）

2024-06-12

·药时代

CAR-T细胞治疗精准打击卵巢癌，新型靶点，超强肿瘤杀伤能力

卵巢癌是女性生殖器官最常见的恶性肿瘤之一，由于早期没有明显的特异性症状，发现时往往已经是晚期，所以被称为“沉默的杀手”，其5年生存率仅为30%左右。尽管大多数患者对手术以及化疗有良好的初始反应，但约80%的女性会复发并最终发展为化疗难治性疾病。所以，几十年来卵巢癌的5年生存率并没有提高太多。因此，迫切需要新的和更好的治疗卵巢癌的方法来改善患者的预后。而CAR-T细胞疗法已被确定为一种新的癌症免疫治疗方法。近日，Clin Transl Immunology杂志发表了题为“Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer”的研究论文，探索了CAR-T细胞疗法在卵巢癌中的潜力。结果显示，靶向nfP2X7的CAR-T细胞可以在体外显著抑制卵巢癌细胞的存活，并且可以显著降低卵巢癌小鼠的肿瘤负荷7-8周，提示nfP2X7-CAR-T细胞作为一种新的卵巢癌免疫疗法具有很大的发展潜力。图源 | onlinelibrary.wiley.com nfP2X7在包括卵巢癌细胞在内的许多恶性细胞表面高度表达，这也是研究人员选择这一标记物作为CAR-T细胞的靶点原因。在成功构建nfP2X7-CAR-T细胞后，研究人员分别在单层培养、3D球体培养和小鼠实验中确认了靶向nfP2X7 CAR-T细胞对卵巢癌细胞的攻击杀伤能力。单层培养的nfP2X7 CAR-T细胞对卵巢癌细胞具有细胞毒性在此实验中，研究人员将卵巢癌细胞单层涂覆，24 h后加入靶向nfP2X7的CAR-T细胞或对照细胞，共培养48h后测定剩余卵巢癌细胞的存活率。与供体匹配的对照细胞相比，靶向nfp2x7的CAR-T细胞显著降低了两种卵巢癌细胞的存活率。 nfP2X7 CAR-T细胞对单层培养卵巢癌细胞存活的影响图源 | onlinelibrary.wiley.com 体外三维球形培养nfP2X7 CAR-T细胞对卵巢癌具有细胞毒性多达三分之一的卵巢癌患者在诊断时，大多数复发的卵巢癌患者会发生恶性腹水。腹水含有多细胞球体，富含肿瘤干细胞样细胞，参与卵巢癌转移和化疗耐药。因此，使用原发性卵巢癌的3D球体培养物来评估nfP2X7 CAR-T细胞的抗肿瘤活性是很重要的，因为它更能代表体内的卵巢癌。在本实验中，体外三维球形培养结果中显示nfP2X7 CAR-T细胞治疗显著降低了5例患者原发性卵巢癌球体大小。表明nfP2X7 CAR-T细胞在体外对3D球体培养的原发性卵巢癌细胞具有显著的抗肿瘤活性。 nfP2X7 CAR-T细胞处理球体大小减小图源 | onlinelibrary.wiley.com nfP2X7 CAR-T细胞抑制卵巢癌小鼠的肿瘤生长接下来，研究者在卵巢癌异种移植小鼠模型中研究了nfP2X7 CAR-T细胞治疗的体内抗肿瘤效果。在肿瘤后第21天，通过腹腔注射给药nfP2X7 CAR-T细胞。在D13时，对照细胞相比，用nfP2X7 CAR-T细胞治疗的小鼠的肿瘤负荷显著降低。在第二批实验中，nfP2X7 CAR-T细胞显著抑制肿瘤生长长达56天。小鼠nfP2X7CAR-T CD3细胞治疗后(第13-64天)的代表性图像图源 | onlinelibrary.wiley.com 结语卵巢癌作为常见的妇科肿瘤，常被称为“沉默的杀手”，早期无明显症状，容易被忽视，一旦出现腹胀、腹痛、肠胃不适、疲劳乏力、消瘦等症状时，已属肿瘤晚期，预后极差。本研究表明，nfP2X7具有成为卵巢癌患者CAR-T细胞免疫治疗成功靶点的巨大潜力。未来的研究需要使用患者来源的异种移植物来支持卵巢癌患者的nfP2X7 CAR-T细胞治疗的发展。参考文献： Veronika Bandara , Victoria M Niktaras , Vasiliki J Willett , et.al. Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer. Clin Transl Immunology . 2024 May 23;13(5):e1512. doi: 10.1002/cti2.1512. eCollection 2024. PMID: 38800555. 封面图来源：123rf 版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 礼来D药：虽全票通过，但仍有“忧患”...... FDA资料来了！今晚9点，礼来重磅阿尔茨海默病新药Donanemab接受新一轮考验重磅！FDA即将就礼来阿尔茨海默病新药Donanemab召开专家咨询委员会会议点击这里，发现价值信息！

免疫疗法细胞疗法

2023-09-25

·生物谷

Nature Communications：靶向nfP2X7的CAR-T细胞有可能成为治疗人类实体瘤的广谱癌症免疫疗法

免疫疗法--使癌症患者自身的免疫细胞能够识别和攻击他们的肿瘤，代表了癌症治疗的范式转变。这一转变是朝着个性化治疗的方向发展，这种治疗不需要广泛的治疗，如化疗就能达到临床终点。免疫疗法--使癌症患者自身的免疫细胞能够识别和攻击他们的肿瘤，代表了癌症治疗的范式转变。这一转变是朝着个性化治疗的方向发展，这种治疗不需要广泛的治疗，如化疗就能达到临床终点。这些免疫疗法使免疫细胞能够特异性地识别和摧毁恶性细胞，这需要严格的监管，以防止对健康组织的附带损害。一种很有前景的免疫治疗方法是嵌合抗原受体(CAR)-T细胞治疗，它将单克隆抗体的抗原特异性结合特性与T细胞的杀伤和自我更新能力结合起来。CAR-T细胞平台的优雅简单性在于，它结合了以MHC不依赖的方式使用抗体样结合域靶向未处理抗原的能力，以及启动T细胞细胞毒活性所需的细胞内信号传递。图片来源：https://doi.org/10.1038/s41467-023-41338-y 近日，来自澳大利亚阿德莱德大学的研究者们在Nature Communications杂志上发表了题为“Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7”的文章，该研究揭示了靶向nfP2X7的泛癌CAR-T细胞免疫治疗的临床前验证。嵌合抗原受体(CAR)-T细胞免疫疗法是一种新型的治疗方法，它通过基因修饰患者自身的T细胞来靶向并杀伤肿瘤细胞。然而，鉴定在多种实体癌类型上表达的U-R-S表面抗原，仍然是一个重大挑战。 P2X嘌呤受体7(P2X7)是一种细胞表面表达的三磷酸腺苷门控阳离子通道，是一种P2X7、P2X7。研究者提出了一个针对nfP2X7的原型-人CAR-T结构，该结构对12种实体肿瘤(乳腺癌、前列腺癌、肺癌、结直肠癌、脑和皮肤)具有潜在的抗原特异性细胞毒作用。在乳腺癌和前列腺癌的异种移植小鼠模型中，靶向nfP2X7的CAR-T细胞显示出强大的抗肿瘤效果。这些数据表明，nfP2X7是一个合适的免疫治疗靶点，因为它在人类肿瘤上广泛表达。靶向nfP2X7的CAR-T细胞有可能成为治疗人类实体瘤的广谱癌症免疫疗法。在NSG小鼠的肿瘤中很容易检测到CAR-T细胞图片来源：https://doi.org/10.1038/s41467-023-41338-y 本研究结果清楚地强调了以CAR-T细胞为靶点的nfP2X7作为一种新的免疫疗法治疗多种实体癌类型的潜力。这项研究首次证明了nfP2X7作为广泛表达nfP2X7的实体瘤的细胞免疫治疗靶点的巨大潜力，并且CAR-T细胞模式可能提供了一种用单抗靶向nfP2X7的功能性替代方案。事实上，在针对实体肿瘤的CAR-T细胞研究中，在NSG小鼠中很少看到肿瘤排斥或治愈，在这些研究中，小鼠只接受CAR-T细胞，而没有额外的治疗(例如检查点抑制剂、放射治疗、IL-2给药)，或者没有对肿瘤细胞进行修饰。进一步提高nfP2X7靶向CAR-T细胞临床疗效的方法可能涉及与标准手术和/或化疗方案或检查点抑制剂联合给药。（生物谷 Bioon.com）参考文献 Veronika Bandara et al. Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7. Nat Commun. 2023 Sep 8;14(1):5546. doi: 10.1038/s41467-023-41338-y.