Phase I study of Clostridium novyi-NT spores in solid tumor cancer patients

诺维梭菌-NT 孢子在实体瘤癌症患者中的 I 期研究

• 批准号: 7656629
• 负责人: Luis A Diaz
• 金额: $ 31.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656629
• 关键词: Anaerobic Bacteria; Animal Model; Animals; Antibiotics; Antibodies; Antibody Formation; Area; Attenuated; Bacteria; Bacterial Infections; Bacterial Spores; Bacteriophages; Biodistribution; Biological Assay; Blood; Cancer Patient; Cell physiology; Clinical; Clinical Data; Clinical Protocols; Clinical Trials; Clostridium; Development; Dimensions; Dose; Dose-Limiting; Drug Formulations; Drug Kinetics; Evaluation; Experimental Neoplasms; FDA approved; Future; Genes; Human; Hydration status; Hypersensitivity; Hypoxia; Immune response; Immunocompetent; Inflammatory; Inflammatory Response; Intravenous; Laboratories; Life; Malignant - descriptor; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Modality; Molecular; Mus; Necrosis; Nude Mice; Nutrient; Organism; Oryctolagus cuniculus; Oxygen; Oxygen measurement, partial pressure, arterial; Pathologic; Patients; Pharmacology; Phase; Phase I Clinical Trials; Processed Genes; Production; Property; Protocols documentation; Public Health; Radiation; Radioactive; Refractory; Reproduction spores; Research; Research Personnel; Safety; Sampling; Solid Neoplasm; Sterility; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Toxin; Tumor Tissue; Vascular blood supply; anthrax lethal factor; assay development; base; chemotherapeutic agent; chemotherapy; clinical efficacy; conventional therapy; cytokine; gene therapy; intravenous injection; man; novel; novel therapeutics; pre-clinical; programs; safety study; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Strategies that successfully target and destroy human cancers must recognize differences between normal and malignant tissues. In this regard, an abnormal vasculature is being increasingly recognized as a consistent feature of solid tumors and a potential point of attack. Malignant solid tumors are generally comprised of a hypoxic, often necrotic core and a viable rim. The core has a poor vascular supply and is therefore deficient in nutrients and oxygen. Therapeutic interventions to date have focused on the well-vascularized outer shell of the tumor, as these are most susceptible to chemotherapeutic agents and radiation. In contrast, few therapies, target the inner, hypoxic core, which can make up a major part of the tumor's mass. For this purpose, we have investigated the potential of using live anaerobic bacteria. In particular, we developed a strain, termed Clostridium novyi-NT(C. novyi-NT), that is a spore-forming Gram-positive anaerobe whose toxicity was attenuated by eliminating a bacteriophage that carried its systemic toxin gene. C. novyi-NT has undergone pre-clinical efficacy and toxicity evaluations in several animal models. C. novyi-NT spores delivered through a single intravenous dose to mice results in substantial tumor regressions in most animal models. Cure rates of 20-30% are common when spores are used alone in immunocompetent mice or rabbits. In nude mice bearing human tumor xenografts, complete regressions are generally observed, and cures are routinely obtained when the spores are administered with selected radiation and chemotherapeutic protocols. Toxicity studies demonstrated no clinical toxicity and minimal pathologic toxicity in healthy animals. While toxicity in tumor-bearing animals was evident in mice, it was manageable with hydration or antibiotics. In this R01 application, we propose a first-in-man phase I clinical trial of C. novyi-NT spores in treatment- refractory solid tumors. We plan to (1) optimize the production of clinical-grade (GMP) C. novyi-NT spores, (2) conduct the phase I clinical trial for safety and efficacy, (3) measure the antibody and systemic inflammatory response to C. novyi-NT in humans, and (4) develop assays to evaluate C. novyi-NT spore pharmacokinetics in humans. Relevance to Public Health: The studies described in this application will evaluate a novel therapeutic strategy in patients with solid tumor malignancies and provide a detailed understanding of the safety, pharmacology and efficacy of live anaerobic bacterial spores in cancer patients.

描述(由申请人提供)：成功靶向和摧毁人类癌症的策略必须认识到正常组织和恶性组织之间的差异。在这一点上，异常的血管系统越来越被认为是实体肿瘤的一贯特征和潜在的侵袭点。恶性实体瘤通常由缺氧的、通常是坏死的核心和有活力的边缘组成。核心的血管供应很差，因此缺乏营养和氧气。到目前为止，治疗干预措施主要集中在血管良好的肿瘤外壳，因为这些外壳最容易受到化疗药物和辐射的影响。相比之下，很少有治疗方法针对内部缺氧的核心，它可以构成肿瘤质量的主要部分。为此，我们调查了使用活厌氧细菌的可能性。特别是，我们开发了一株名为Clostridium novyi-NT(C.novyi-NT)的菌株，这是一种形成孢子的革兰氏阳性厌氧菌，其毒性通过消除携带其系统毒素基因的噬菌体而减弱。C.novyi-NT已经在几个动物模型上进行了临床前疗效和毒性评估。在大多数动物模型中，通过一次静脉注射将C.novyi-NT孢子传递给小鼠会导致肿瘤的实质性消退。在具有免疫能力的小鼠或兔子中单独使用孢子时，治愈率通常为20%-30%。在携带人类肿瘤异种移植瘤的裸鼠身上，通常可以观察到完全消退，当孢子以选定的放射和化疗方案给予时，通常可以获得治愈。毒性研究表明，在健康动物身上没有临床毒性和最低的病理毒性。虽然对荷瘤动物的毒性在小鼠身上很明显，但可以通过水合或抗生素来控制。在R01的应用中，我们提出了一项治疗难治性实体肿瘤的新冠冠状杆菌孢子的I期临床试验。我们计划(1)优化临床(GMP)新冠沙门氏菌孢子的生产，(2)进行安全性和有效性的I期临床试验，(3)测定人类对新冠沙门氏菌的抗体和全身炎症反应，(4)建立评估新冠沙门氏菌孢子在人类体内的药代动力学的方法。与公共健康相关：本申请中描述的研究将评估实体肿瘤恶性肿瘤患者的一种新的治疗策略，并详细了解活的厌氧细菌孢子在癌症患者中的安全性、药理学和有效性。