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

描述（由申请人提供）：成功靶向和摧毁人类癌症的策略必须识别正常和恶性组织之间的差异。在这方面，异常的血管系统越来越被认为是实体瘤的一贯特征和潜在的攻击点。恶性实体瘤通常由缺氧、坏死的核心和活的边缘组成。核心的血管供应很差，因此缺乏营养和氧气。迄今为止，治疗干预主要集中在血管化良好的肿瘤外壳，因为这些部位最容易受到化疗药物和放疗的影响。相比之下，很少有治疗方法是针对内部的，缺氧的核心，这可以构成肿瘤肿块的主要部分。为此，我们研究了使用活的厌氧细菌的潜力。特别是，我们开发了一种菌株，称为新梭状芽胞杆菌- nt (C。novyi-NT)，这是一种孢子形成的革兰氏阳性厌氧菌，其毒性通过消除携带全身毒素基因的噬菌体而减弱。C. novyi-NT在几种动物模型中进行了临床前疗效和毒性评估。在大多数动物模型中，通过单次静脉给药给小鼠C. novyi-NT孢子可导致肿瘤明显消退。当孢子单独用于免疫能力强的小鼠或兔子时，治愈率通常为20-30%。在携带人类肿瘤异种移植物的裸鼠中，通常可以观察到完全的消退，并且当使用选定的放射和化疗方案给予孢子时，通常可以获得治愈。毒性研究表明，对健康动物无临床毒性和最小的病理毒性。虽然对荷瘤动物的毒性在小鼠身上很明显，但用水合作用或抗生素是可以控制的。在这个R01申请中，我们提出了C. novyi-NT孢子治疗难治性实体瘤的首个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)进行安全性和有效性的I期临床试验，(3)测量人体对C. novyi-NT的抗体和全身炎症反应，以及(4)开发评估人体C. novyi-NT孢子药代动力学的检测方法。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一种新的治疗策略，并提供对癌症患者使用活厌氧细菌孢子的安全性、药理学和有效性的详细了解。

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.