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

基于鼠伤寒沙门氏菌的孤儿良性肿瘤细菌疗法：II 型神经纤维瘤病 (NF2)

• 批准号: 10267742
• 负责人: GARY JAY BRENNER
• 金额: $ 19.86万
• 依托单位: MULBERRY BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267742
• 关键词: Acoustic Neuroma; Adolescence; Affect; Age; Allografting; Animal Model; Applications Grants; Area; Attenuated; Bacteria; Benign; Benign Schwannoma; Biodistribution; Biological; Blood Vessels; Brain Stem; Caring; Cause of Death; Cells; Cessation of life; Clinical Data; Clinical Treatment; Clinical Trials; Data; Development; Disease; Distal; Engineering; Ependymoma; Equilibrium; Excision; FDA approved; Facial paralysis; Future; Generations; Goals; Grant; Growth; Hearing; Human; Hypoxia; Immune; Immune response; Immunologics; In Vitro; Individual; Injections; Intervention; Investigational New Drug Application; Lead; Lesion; Life; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Medical; Medicine; Memory; Modeling; Morbidity - disease rate; Mus; Mycobacterium bovis; NF1 gene; Neoplasms; Nerve; Nervous System Trauma; Neurilemmoma; Neurofibromatosis 2; Neurosurgeon; Operative Surgical Procedures; Orphan; Otolaryngologist; Pain; Parents; Patients; Peripheral Nervous System; Pharmacologic Substance; Phase; Physicians; Production; Property; Radiation therapy; Resected; Risk; Safety; Sales; Salmonella; Salmonella typhimurium; Sensory; Small Business Technology Transfer Research; Testing; Therapeutic Effect; Tissues; Toxic effect; Toxicology; Translations; Tumor Cell Invasion; Tumor Immunity; Ultrasonography; Validation; Virus; Walking; Work; Xenograft procedure; adaptive immune response; base; cancer therapy; cell killing; chemotherapeutic agent; cytokine; cytotoxic; cytotoxicity; deafness; efficacy testing; emerging adult; hearing impairment; high risk; image guided; in vivo; innovation; macrophage; meningioma; mortality; motor disorder; nanobodies; neoplastic cell; neurofibroma; next generation; non-muscle invasive bladder cancer; novel; novel therapeutics; pre-clinical; prevent; programmed cell death ligand 1; radiologist; rare genetic disorder; response; safety engineering; success; tumor

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.

2 型神经纤维瘤病 (NF2) 是一种罕见的遗传性疾病，全球约 25,000 人中就有 1 人受到影响。 虽然这些肿瘤通常是良性的，但会导致受影响个体严重的发病率和死亡率。几乎所有 NF2 患者失去听力，许多人失去行走能力，甚至失去视力。 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 是孤儿适应症 代表了一项重大的未满足的医疗需求，从而支持 FDA 快速通道指定。 NF生物估计 NF2 商业机会年峰值销售额超过 10 亿美元。 NF2 治疗的成功也将 导致对其他良性和神经鞘瘤相关肿瘤（如 NF1）进行检测。 手术切除和放射治疗是当前的护理标准。然而，这些治疗方法有很大的 限制。切除可导致严重的感觉丧失，包括耳聋、疼痛、面瘫和运动能力 功能障碍。由于存在神经或脑干损伤的风险，切除术也不总是可能的。放射治疗 由于存在恶性转化的风险，可能会被禁忌，并且通常不会消除 神经鞘瘤。受影响的个体通常患有多发性神经鞘瘤，肿瘤在一生中都会出现， 进一步增加与疾病相关的痛苦并限制手术切除的效用。没有经过批准的 药物治疗和有限的临床试验管道。 NF Bio 开发了一种 NF2 细菌疗法，利用瘤内 (i.t.) 注射减毒的金黄色葡萄球菌。 鼠伤寒，由神经外科医生、耳鼻喉科医生以图像引导方式（MRI 或超声波）进行治疗， 疼痛医学医师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 沙门氏菌在高度血管化组织的缺氧区域大量繁殖，这是 NF2 的标志 神经鞘瘤，其抗肿瘤细胞毒性机制不需要肿瘤细胞复制。 NF Bio 是第一个开发基于细菌的疗法来治疗 NF2 的公司。我们已经在动物身上证明了 它的模型注射减毒鼠伤寒沙门氏菌可通过直接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，它还能诱导针对远端的全身免疫反应 肿瘤和阻止新病变进一步发展的记忆反应。这种干预措施的效果较低 由于靶向机制和工程安全性，神经系统损伤的风险高于手术切除 本提案中将制定的机制。 在拟议的一期工作中，NF Bio 将开发一种增强直接肿瘤治疗的下一代细菌疗法 杀伤并诱导免疫介导的杀伤。在未来的第二阶段资助工作中，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 研究性新药 (IND) 申请。