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

摘要 Aumenta正在开发一种来自两种共生细菌物种的产品，用于创新 免疫疗法。该产品旨在增强免疫系统的多个手臂，提供 用于治疗传染病(例如真菌感染)中未得到满足的需求的安全、新颖和创新的治疗方法 增强身体对免疫肿瘤疗法的反应(例如，针对黑色素瘤的免疫检查点疗法， 结直肠癌)。100多年前，科利毒素，一种热致死的化脓性链球菌和 粘质沙雷氏菌被用来刺激免疫系统，经常导致肿瘤消退， 尽管它有败血症的风险。来自临床前模型、人类患者相关性研究和早期研究的证据 粪便微生物区系移植(FMT)临床试验表明，利用肠道微生物区系是一种可行的策略 增强宿主的免疫反应。免疫系统刺激有可能提高患者的疗效 癌症患者的免疫检查点治疗。与癌症类似，多种病原体利用 免疫检查站，以逃避免疫控制，包括疟疾、艾滋病毒和乙肝。信息和通信技术的使用还 对治疗真菌感染特别感兴趣，如毛霉病、曲霉病和念珠菌病 免疫功能受损的病人。然而，目前微生物组疗法的范例--即口服 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 对将活生物引入患者的担忧，以及潜在的FDA监管障碍。要克服 这些挑战，Aumenta的产品是从两种共生肠道细菌的裂解物中提取出来的 对成年黑色素瘤患者ICT呈阳性反应的革兰氏阴性杆菌 (Bt)和革兰氏阳性普氏杆菌(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手臂 (PAMPS)调节免疫反应，启动CD4和CD8 T细胞反应。在建议的 工作中，我们计划1)确定健康小鼠的最大耐受量和BFML在健康小鼠体内的剂量反应 接受ICT治疗的黑色素瘤和结直肠癌小鼠，2)展示了对人类的可译性 体外和体内模型，以及3)使用点击化学/荧光法确定BFML的生物分布 标记法，将提供有关安全性和作用机制的有价值的信息。成功 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-Enabling 研究，并开始规划我们的制造、监管和临床试验策略。增强免疫力 像BFML这样的微生物疗法有可能将免疫疗法的疗效扩大到更多的 并为治疗具有挑战性的感染开辟新的途径。

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.