Designer EcN for treatment of solid tumors

用于治疗实体瘤的 Designer EcN

基本信息

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
项目类别：
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

项目摘要

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.

当前治疗实体瘤的方式包括手术切除，化学疗法和放射线，通常不足以治愈的方法，通常与许多副作用有关。基于免疫疗法的干预措施，包括阻断免疫的免疫刺激单克隆抗体检查站，正在彻底改变癌症的治疗，因为它们提供了一种让患者参与的手段免疫系统识别和抗击癌症。但是，这些疗法的系统给药通常是与明显的广告反应相关，可能非常严重，尤其是在使用多个代理商时结合。新颖的方法是将免疫刺激分子直接递送到肿瘤的有效递送需要和肿瘤沉积物。有趣的是，多种细菌种类有选择地定殖和增殖在肿瘤中的高滴度，其中一些像沙门氏菌和梭状芽胞杆菌促进肿瘤回归甚至清除，至少部分由诱导的宿主炎症反应。这些细菌的减弱版本是观察到在小鼠模型中有效地放射肿瘤，但在人类试验中的成功有限，可能因为它们可以从全身循环中迅速清除，因此细菌永远不会到达并确定居住在肿瘤中。有趣的是，Nissle 1917 E. Coli（ECN），这是一种常用的益生菌菌株炎症性肠病的治疗，还可以为实体瘤而定。但是，目的地到达滴度 ECN高达1010个菌落形成细菌/克肿瘤的单位，不会影响反应。在这里我们建议 ECN的测试变体能够输送免疫刺激性纳米型，以阻止免疫活性检查点蛋白直接进入实体瘤的微环境。然后，我们将研究这些能力使用黑色素瘤小鼠模型促进肿瘤回归的菌株。我们还将进行全基因组转座子插入筛选以识别ECN确定与固体内的归巢和增殖有关肿瘤。我们的期望，在完成这项探索性的2年赠款后，我们将获得概念证明我们正在开发的可编程免疫细菌疗法具有新颖的潜力癌症治疗平台。