A Novel Bacterially-derived Product to Enhance Immunity and Response to Immune Checkpoint Therapy

一种新型细菌衍生产品，可增强免疫力和对免疫检查点治疗的反应

基本信息

批准号：
10482027
负责人：
ANDREW Y KOH
金额：
$ 28.92万
依托单位：
AUMENTA BIOSCIENCES, INC.
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：
2022-05-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482027
关键词：
Adult Adverse effects Agonist Antibiotics Aspergillosis Award Bacteroides thetaiotaomicron Biochemical Biodistribution Biological Assay Biological Sciences C57BL/6 Mouse CD34 gene CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Candidiasis Cell Wall Chemistry Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Communicable Diseases Correlative Study Data Dendritic Cells Dose Enhancers Ethics Exposure to Face Future Gene Expression Profile Goals HIV Heart Hematopoietic stem cells Hepatitis B Human Immune Immune response Immune system Immunity Immunocompromised Host Immunooncology Immunotherapy Implant In Situ Nick-End Labeling In Vitro Infection Injections Innovative Therapy Interleukin-12 Interleukin-6 Intestines Kidney Label Lactobacillus acidophilus Lead Lipopolysaccharides Liver Lymphocyte MC38 Malaria Malignant Neoplasms Maximum Tolerated Dose Measures Melanoma Cell Methods Modeling Molecular Monoclonal Antibodies Mucormycosis Mus Mycoses Oncology Oral Organ Organism Pathogenicity Pathology Patient-Focused Outcomes Patients Pattern Pattern recognition receptor Phase Pre-Clinical Model Probiotics Proteins Risk Safety Sepsis Serratia marcescens Stains Streptococcus pyogenes T cell response T-Lymphocyte TLR2 gene TLR4 gene TNF gene Testing Therapeutic Time Tissues Toxic effect Toxin Transplantation Work Yogurt anti-CTLA4 anti-PD-1 anti-PD1 antibodies anti-tumor immune response arm bacterial lysate checkpoint inhibition checkpoint therapy commensal bacteria cost effective cytokine design early phase clinical trial experimental study fecal transplantation gut bacteria gut colonization gut microbiota humanized mouse immune checkpoint immunoregulation improved in vivo Model innovation interest intraperitoneal melanoma microbial microbiome microbiome therapeutics next generation novel novel therapeutics pathogen pathogenic bacteria pre-clinical response subcutaneous tumor tumor growth

项目摘要

Abstract Aumenta is developing a product derived from two commensal bacterial species for use as an innovative immunologic therapy. The product is designed to augment multiple arms of the immune system, offering a safe, novel and innovative therapy for unmet needs in treating infectious disease (e.g. fungal infections) and enhancing the body's response to immuno-oncology therapies (e.g. immune checkpoint therapies for melanoma, colorectal cancer). More than 100 years ago, Coley's toxin, a mix of heat-killed Streptococcus pyogenes and Serratia marcescens, was used to stimulate the immune system and frequently resulted in tumor regression, though it carried a risk of sepsis. Evidence from preclinical models, human patient correlative studies, and early fecal microbiota transplant (FMT) clinical trials suggests that utilizing gut microbiota is a viable strategy to enhance the host’s immune response. Immune system stimulation has the potential to improve the efficacy of immune checkpoint therapy (ICT) in cancer patients. Similar to cancers, multiple pathogens take advantage of immune checkpoints to evade immune control, including malaria, HIV and hepatitis B. The use of ICT is also of special interest in treating fungal infections, such as mucormycosis, aspergillosis, and candidiasis in immunocompromised patients. However, the current paradigm of microbiome therapeutics—namely oral probiotics or FMT—is fraught with challenges, including safety, ability to sustain gut colonization, ethical concerns about introducing live organisms into patients, and potential FDA regulatory hurdles. To overcome these challenges, Aumenta’s product is derived from lysates of two commensal gut bacteria associated with a positive response to ICT in adult melanoma patients: the Gram-negative Bacteroides thetaiotaomicron (Bt) and Gram-positive Faecalibacterium prausnitzii (Fp). Through this Bt/Fp microbial lysate (BFML), we aim to augment multiple arms of the immune system via specific bacterial pathogen-associated molecular patterns (PAMPs) that modulate the immune response and that prime CD4 and CD8 T cell responses. In the proposed work, we plan to 1) Determine the maximum tolerated dose in healthy mice and the dose response of BFML in mice with melanoma and colorectal cancer receiving ICT, 2) Demonstrate translatability to humans in relevant in vitro and in vivo models, and 3) Determine the biodistribution of BFML using a click chemistry/fluorescent labeling method, which will provide valuable information on safety and the mechanism of action. Successful completion of these aims will allow Aumenta to seamlessly transition into a Phase II award, initiate IND-enabling studies, and begin planning our manufacturing, regulatory, and clinical trial strategies. Immune-enhancing microbial therapies like BFML have the potential to extend the efficacy of immunotherapy to greater numbers of cancer patients and to open new avenues for treating challenging infections.

抽象的 Aumenta 正在开发一种源自两种共生细菌物种的产品，用作创新药物该产品旨在增强免疫系统的多个分支，提供安全、新颖和创新的疗法，满足治疗传染病（例如真菌感染）方面未满足的需求，以及增强身体对免疫肿瘤疗法的反应（例如黑色素瘤的免疫检查点疗法， 100 多年前，Coley 毒素是一种热灭活的化脓性链球菌和粘质沙雷氏菌用于刺激免疫系统并经常导致肿瘤消退，尽管它具有败血症的风险，但来自临床前模型、人类患者相关研究和早期的证据。粪便微生物群移植 (FMT) 临床试验表明，利用肠道微生物群是一种可行的策略增强宿主的免疫反应有可能提高疗效。癌症患者的免疫检查点疗法（ICT）与癌症类似，多种病原体都会利用这一点。免疫检查点以逃避免疫控制，包括疟疾、艾滋病毒和乙型肝炎。信息通信技术的使用也对治疗真菌感染特别感兴趣，例如毛霉菌病、曲霉病和念珠菌病然而，目前微生物组治疗的范例——即口服疗法益生菌或 FMT——充满挑战，包括安全性、维持肠道定植的能力、伦理对将活体引入患者体内的担忧以及 FDA 潜在的监管障碍需要克服。针对这些挑战，Aumenta 的产品源自两种相关肠道共生细菌的裂解物成年黑色素瘤患者对 ICT 产生积极反应：革兰氏阴性多形拟杆菌 (Bt) 和革兰氏阳性粪杆菌 (Fp) 通过这种 Bt/Fp 微生物裂解物 (BFML)，我们的目标是通过特定的细菌病原体相关分子模式增强免疫系统的多个分支 (PAMP) 调节免疫反应并引发 CD4 和 CD8 T 细胞反应。工作中，我们计划 1) 确定健康小鼠的最大耐受剂量以及 BFML 在患有黑色素瘤和结直肠癌的小鼠接受 ICT，2) 展示相关领域对人类的可翻译性体外和体内模型，以及 3) 使用点击化学/荧光测定 BFML 的生物分布标签方法，这将提供有关安全性和成功作用机制的有价值的信息。完成这些目标将使 Aumenta 能够无缝过渡到第二阶段奖项，启动 IND 支持研究，并开始规划我们的生产、监管和临床试验策略。像 BFML 这样的微生物疗法有可能将免疫疗法的功效扩展到更多的患者癌症患者并开辟治疗挑战性感染的新途径。