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: 7892379
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892379
• 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; phase 1 study; 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）：成功靶向和消灭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。在这方面，异常脉管系统越来越被认为是实体瘤的一致特征和潜在的攻击点。恶性实体瘤通常由缺氧且经常坏死的核心和存活的边缘组成。核心的血管供应较差，因此缺乏营养和氧气。迄今为止的治疗干预措施主要集中在肿瘤血管丰富的外壳上，因为这些外壳最容易受到化疗药物和放射的影响。相比之下，很少有治疗方法针对内部缺氧核心，该核心构成了肿瘤质量的主要部分。为此，我们研究了使用活厌氧细菌的潜力。特别是，我们开发了一种名为诺维梭菌-NT（C. novyi-NT）的菌株，它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 已在多种动物模型中进行了临床前功效和毒性评估。通过单次静脉注射向小鼠输送 C. novyi-NT 孢子，可导致大多数动物模型中的肿瘤显着消退。当孢子单独用于免疫功能正常的小鼠或兔子时，治愈率通常为 20-30%。在携带人类肿瘤异种移植物的裸鼠中，通常观察到完全消退，并且当使用选定的放射和化疗方案施用孢子时通常获得治愈。毒性研究表明，对健康动物没有临床毒性，且病理毒性极小。虽然在小鼠身上对荷瘤动物的毒性很明显，但可以通过水合或抗生素来控制。在此 R01 申请中，我们提出了 C. novyi-NT 孢子治疗难治性实体瘤的首次人体 I 期临床试验。我们计划 (1) 优化临床级 (GMP) C. novyi-NT 孢子的生产，(2) 进行 I 期临床试验以确保安全性和有效性，(3) 测量人体对 C. novyi-NT 的抗体和全身炎症反应，以及 (4) 开发测定法来评估 C. novyi-NT 孢子在人体中的药代动力学。与公共健康的相关性：本申请中描述的研究将评估实体瘤恶性肿瘤患者的新型治疗策略，并详细了解活厌氧细菌孢子在癌症患者中的安全性、药理学和功效。

项目成果

Tumor-targeted delivery of siRNA by non-viral vector: safe and effective cancer therapy.

• DOI: 10.1517/17425240802568505
• 发表时间: 2008-12
• 期刊: Expert opinion on drug delivery
• 影响因子: 6.6
• 作者: Chen Y;Huang L
• 通讯作者: Huang L

Detection of tumor DNA at the margins of colorectal cancer liver metastasis.

• DOI: 10.1158/1078-0432.ccr-10-3087
• 发表时间: 2011-06-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Holdhoff M;Schmidt K;Diehl F;Aggrawal N;Angenendt P;Romans K;Edelstein DL;Torbenson M;Kinzler KW;Vogelstein B;Choti MA;Diaz LA Jr
• 通讯作者: Diaz LA Jr