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细菌的产品， 免疫疗法该产品旨在增强免疫系统的多个分支， 安全、新颖和创新的治疗方法，以满足治疗感染性疾病（如真菌感染）的未满足需求， 增强身体对免疫肿瘤学疗法（例如用于黑素瘤的免疫检查点疗法， 结肠直肠癌）。100多年前，Coley的毒素，一种混合了热杀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， 尽管有感染败血症的风险来自临床前模型、人类患者相关研究和早期 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免疫系统刺激有可能提高免疫抑制剂的功效。 免疫检查点疗法（ICT）在癌症患者中的应用与癌症相似，多种病原体利用 免疫检查点，以逃避免疫控制，包括疟疾，艾滋病毒和肝炎B。信息和通信技术的使用也是 特别感兴趣的是治疗真菌感染，如毛霉菌病，曲霉病和念珠菌病， 免疫功能低下的患者。然而，目前的微生物组治疗范式-即口服 益生菌或FMT-充满了挑战，包括安全性，维持肠道定植的能力，伦理 对将活生物体引入患者的担忧，以及潜在的FDA监管障碍。克服 面对这些挑战，Aumenta的产品来自两种肠道细菌的裂解物， 在成人黑色素瘤患者中对ICT有阳性反应：革兰氏阴性多形拟杆菌 (Bt)和革兰氏阳性普氏粪杆菌（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是调节免疫应答并引发CD 4和CD 8 T细胞应答的PAMP。拟议 工作，我们计划1）确定健康小鼠的最大耐受剂量和BFML的剂量反应， 接受ICT的患有黑素瘤和结肠直肠癌的小鼠，2）在相关研究中证明对人类的可翻译性， 体外和体内模型，和3）使用点击化学/荧光免疫分析测定BFML的生物分布。 标记方法，这将提供有关安全性和作用机制的有价值的信息。成功 这些目标的完成将使Aumenta能够无缝地过渡到第二阶段合同，启动IND启用 研究，并开始规划我们的生产、监管和临床试验策略。免疫增强 像BFML这样的微生物疗法有可能将免疫疗法的疗效扩展到更多的患者。 癌症患者，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.