Salmonella typhimurium-based Bacteriotherapy for Orphan Benign Tumors: Neurofibromatosis Type II (NF2)

2型神经纤维瘤病(NF2)是一种罕见的遗传性疾病，全球每25,000人中就有1人受到影响。 虽然这些肿瘤通常是良性的，但在受影响的个人中会导致严重的发病率和死亡率。几乎所有NF2 患者失去听力，许多人失去行走甚至看东西的能力。NF2患者的平均死亡年龄 36岁，其中许多人在青春期或成年早期死于疾病。NF2是一个孤立的症状 并代表了一个主要的未得到满足的医疗需求，因此支持FDA的快速通道指定。NFBio估计 NF2的商业机会将在年度销售高峰年超过10亿美元。NF2治疗的成功也将 导致在其他良性和神经鞘瘤相关的肿瘤中进行检测，如NF1。 手术切除和放射治疗是目前的护理标准。然而，这些治疗方法有主要的 限制。切除会导致严重的感觉丧失，包括耳聋、疼痛、面瘫和运动。 功能障碍。由于神经或脑干损伤的风险，切除也不总是可能的。放射治疗 由于恶性转化的风险而可能是禁忌症，并且通常不会消除 神经鞘瘤。受影响的人通常有多发性神经鞘瘤，肿瘤在一生中都会出现， 进一步增加与疾病相关的痛苦，限制手术切除的效用。没有已审批的 药物治疗和有限的临床试验管道。 NF Bio已经开发出一种利用肿瘤内(I.T.)的NF2细菌疗法。注射减毒S。 小鼠，由神经外科医生、耳鼻喉科医生以图像引导的方式(MRI或超声波)提供， 疼痛内科医生或介入放射科医生使用这种细菌疗法治疗神经鞘瘤是合理的。 事实上，沙门氏菌在高度血管化的组织的缺氧区茁壮成长，这是NF2的标志 神经鞘瘤及其抗肿瘤细胞毒机制不需要肿瘤细胞复制。 NF Bio是第一个开发出治疗NF2的细菌疗法的公司。我们已经在动物身上展示了 IT的模型。注射减毒鼠伤寒沙门氏菌可通过直接注射减少注射肿瘤的体积 细胞毒性和抗血管生成作用；重要的是，它还诱导针对远端的全身性免疫反应。 肿瘤和防止新病变进一步发展的记忆反应。这一干预具有较低的 由于靶向机制和工程安全，神经损伤的风险高于手术切除 将在这项提案中制定的机制。 在拟议的第一阶段工作中，NF Bio将开发一种下一代细菌疗法，以增强直接肿瘤 杀戮和诱导免疫介导的杀戮。在未来的第二阶段拨款工作中，我们将选择一名开发候选人 (DC)基于体外和体内数据，并进行毒理学和生物分布研究，以使美国 研究用新药(IND)申请。

Neurofibromatosis type 2 (NF2) is a rare genetic disorder that affects about 1 in 25,000 individuals globally. While usually benign, these tumors result in severe morbidity and mortality in affected individuals. Almost all NF2 patients lose their hearing, and many lose the ability to walk and even to see. NF2 patients’ average age at death is 36 years, many of whom die in adolescence or early adulthood from their disease. NF2 is an orphan indication and represents a major unmet medical need, thus supporting an FDA Fast Track designation. NF Bio estimates the NF2 commercial opportunity to exceed US$1B in annual peak year sales. Success in NF2 treatment will also lead to testing in other benign and schwannoma-related neoplasms such as NF1. Operative resection and radiotherapy are the current standards of care. However, these treatments have major limitations. Resection can lead to a significant sensory loss including deafness, pain, facial paralysis, and motor dysfunction. Resection also is not always possible due to the risk of nerve or brain stem damage. Radiotherapy can be contraindicated due to the risk of malignant transformation and typically does not eliminate the schwannoma. Affected individuals typically have multiple schwannomas with tumors arising throughout life, further increasing disease-associated suffering and limiting the utility of surgical resection. There is no approved pharmaceutical therapy and a limited clinical trial pipeline. NF Bio has developed an NF2 bacteriotherapy that utilizes intra-tumoral (i.t.) injection of attenuated S. typhimurium, delivered in an image-guided fashion (MRI or ultrasound) by neurosurgeons, otolaryngologists, pain medicine physicians, or interventional radiologists Use of this bacterial therapy for schwannomas is justified by the fact that Salmonella thrives in the hypoxic areas of highly vascularized tissues, which is a hallmark of NF2 schwannomas, and its anti-tumor cytotoxic mechanisms do not require tumor cell replication. NF Bio is the first to develop a bacteria-based therapy for the treatment of NF2. We have demonstrated in animal models that i.t. injection of attenuated S. typhimurium decreases the volume of the injected tumor through direct cytotoxic and anti-angiogenic effects; importantly, it also induces a systemic immune response that targets distal tumors and a memory response that prevents further development of new lesions. This intervention has a lower risk of neurologic damage than operative resection due to the targeting mechanisms and engineered safety mechanisms that will be developed in this proposal. In the proposed Phase I work, NF Bio will develop a next-generation bacterial therapy that enhances direct tumor killing and induce immune-mediated killing. In future Phase II grant work, we will select a Development Candidate (DC) based on in vitro and in vivo data, and conduct toxicology and biodistribution studies to enable a US Investigational New Drug (IND) application.