Designer EcN for treatment of solid tumors

用于治疗实体瘤的 Designer EcN

• 批准号: 10459848
• 负责人: CAMMIE LESSER
• 金额: $ 24.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459848
• 关键词: Address; Adverse reactions; Antibodies; Area; Attenuated; Bacteria; Blocking Antibodies; Blood Circulation; Chemotherapy and/or radiation; Colon Carcinoma; Colony-forming units; Deposition; Development; Disease; Drug Delivery Systems; Engineering; Ensure; Escherichia coli; Excision; Future; Goals; Gram-Negative Bacteria; Grant; Home; Homing; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunotherapy; Infiltration; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Lead; Lymphoma; MC38; Malignant Neoplasms; Mammalian Cell; Mediating; Modality; Monoclonal Antibodies; N-terminal; Neoplasms; Operative Surgical Procedures; Pathogenicity; Pathway interactions; Patients; Probiotics; Proliferating; Proteins; Public Health; Research; Safety; Salmonella; Site; Solid Neoplasm; Specificity; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Type III Secretion System Pathway; Variant; Work; anti-CTLA4; anti-PD-L1; anti-tumor immune response; base; cancer therapy; comparative efficacy; cytokine; cytotoxic; expectation; fighting; genome wide screen; genome-wide; immune checkpoint; immune checkpoint blockade; improved; interest; melanoma; mouse model; nanobodies; nanomachine; neoplastic; novel; novel therapeutics; programs; residence; response; side effect; success; synthetic biology; targeted delivery; therapeutic protein; treatment response; tumor; tumor microenvironment

Current modalities for the treatment of solid tumors include surgical resection, chemotherapy, and radiation, approaches that often are not sufficient to lead to cure and are generally associated with numerous side effects. Immunotherapy based interventions, including immunostimulatory monoclonal antibodies that block immune checkpoints, are revolutionizing the treatment of cancers as they provide a means to engage the patient’s own immune system to recognize and fight cancer. However, the systemic administration of these therapies is often associated with marked adverse reactions that can be very serious, particularly when multiple agents are used in combination. Novel means to target the efficient delivery of immunostimulatory molecules directly to tumors and neoplasmic deposits are needed. Interestingly, multiple bacterial species selectively colonize and proliferate to high titers in tumors where some like Salmonella and Clostridial species promote tumor regression and even clearance, at least in part by inducing host inflammatory responses. Attenuated versions of these bacteria are observed to effectively eradicate tumors in mouse models, but have shown limited success in human trials, likely because they are rapidly cleared from the systemic circulation such that the bacteria never reach and establish residence in the tumors. Interestingly, Nissle 1917 E. coli (EcN), a probiotic strain commonly used in the treatment of inflammatory bowel disease, also homes to and colonizes solid tumors. Yet, despite reaching titers as high as 1010 colony forming units of bacteria/gram of tumor, EcN induces no response. Here we propose to test variants of EcN capable of delivering immunostimulatory nanobodies that block that activity of immune checkpoint proteins directly into the microenvironment of solid tumors. We will then investigate the ability of these strains to promote tumor regression using a mouse model of melanoma. We will also conduct genome-wide transposon insertion screens to identify EcN determinants involved in the homing to and proliferation within solid tumors. It is our expectation that at the completion of this exploratory 2-year grant we will have proof-of-concept that the programmable immune-based bacteriotherapy we are developing has the potential to become a novel cancer therapeutics platform.

目前治疗实体瘤的方法包括手术切除、化疗和放疗， 这些方法通常不足以治愈疾病，并且通常会产生许多副作用。 基于免疫疗法的干预措施，包括阻断免疫的免疫刺激性单克隆抗体 检查站正在彻底改变癌症的治疗，因为它们提供了一种让患者自己参与的方法 免疫系统识别和对抗癌症。然而，这些疗法的全身给药通常是 与可能非常严重的明显不良反应相关，特别是在使用多种药物时 组合起来。将免疫刺激分子直接有效递送至肿瘤的新方法 并且需要肿瘤沉积物。有趣的是，多种细菌选择性地定植和增殖 在肿瘤中达到高滴度，其中沙门氏菌和梭状芽孢杆菌等物种可促进肿瘤消退，甚至 清除，至少部分是通过诱导宿主炎症反应。这些细菌的减毒版本是 在小鼠模型中观察到可有效根除肿瘤，但在人体试验中显示的成功有限，可能 因为它们会迅速从体循环中清除，因此细菌永远不会到达并建立 居住在肿瘤中。有趣的是，Nissle 1917 大肠杆菌 (EcN) 是一种常用于 治疗炎症性肠病，也是实体瘤的家园和定殖。然而，尽管达到滴度 高达 1010 个细菌菌落形成单位/克肿瘤时，EcN 不会引起任何反应。在此我们建议 测试 EcN 的变体，能够传递免疫刺激性纳米抗体，从而阻断免疫活性 检查点蛋白直接进入实体瘤的微环境。然后我们将调查这些人的能力 使用黑色素瘤小鼠模型促进肿瘤消退的菌株。我们还将进行全基因组 转座子插入筛选，以确定参与固体归巢和增殖的 EcN 决定簇 肿瘤。我们期望在完成这项为期 2 年的探索性资助后，我们将获得概念验证 我们正在开发的基于可编程免疫的细菌疗法有潜力成为一种新型的 癌症治疗平台。