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

描述（由申请人提供）：成功靶向和破坏人类癌症的策略必须识别正常组织和恶性组织之间的差异。在这方面，异常血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、经常坏死的核心和有活力的边缘组成。核心的血管供应不足，因此缺乏营养和氧气。迄今为止，治疗干预集中在肿瘤的血管化良好的外壳上，因为这些外壳对化疗剂和放射最敏感。相比之下，很少有疗法针对内部缺氧核心，这可能构成肿瘤质量的主要部分。为此，我们研究了使用活厌氧菌的潜力。特别是，我们开发了一种菌株，称为诺氏梭菌-NT（C。novyi-NT），其是形成孢子的革兰氏阳性厌氧菌，其毒性通过消除携带其全身毒素基因的噬菌体而减弱。C. novyi-NT已经在几种动物模型中进行了临床前疗效和毒性评价。C.通过单次静脉内剂量递送给小鼠的诺氏-NT孢子在大多数动物模型中导致实质性肿瘤消退。当孢子单独用于免疫活性小鼠或兔子时，20-30%的治愈率是常见的。在携带人肿瘤异种移植物的裸鼠中，通常观察到完全消退，并且当孢子与选择的放射和化学治疗方案一起施用时，常规地获得治愈。毒性研究表明，在健康动物中无临床毒性和极轻微的病理毒性。虽然在小鼠中对荷瘤动物的毒性很明显，但可以通过水合作用或抗生素来控制。在R 01申请中，我们提出了一个首次在人体I期临床试验的C。Novyi-NT孢子在难治性实体瘤中的应用我们计划（1）优化临床级（GMP）C的生产。诺氏-NT孢子，（2）进行I期临床试验的安全性和有效性，（3）测量抗体和全身炎症反应。novyi-NT在人体中的应用，以及（4）开发用于评估C.诺氏-NT孢子在人体内的药代动力学。与公共卫生的相关性：本申请中描述的研究将评估恶性实体瘤患者的新型治疗策略，并详细了解活厌氧菌孢子在癌症患者中的安全性、药理学和疗效。

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.