A Novel Microbiome-Based Immune-Modulator that Potentiates Cancer Checkpoint Therapy

一种新型的基于微生物组的免疫调节剂，可增强癌症检查点治疗

基本信息

批准号：
10657818
负责人：
Gary Fanger
金额：
$ 82.81万
依托单位：
RISE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657818
关键词：
Animals Antigens Bacteria Biological Biological Assay CTLA4 gene Cancer Patient Capital Clinical Clinical Research Clinical Trials DNA cassette Development Disease Dose Drug Kinetics Drug Synergism Drug resistance Effectiveness Engineered Probiotics Engineering Enterococcus Enterococcus faecium Enzymes Food production Funding Future Genetic Engineering Genome Goals Growth Health Homeostasis Human Hydrolase Immune Immune checkpoint inhibitor Immune signaling Immunologics Immunomodulators Immunooncology Immunotherapy Industry Intestines Investments Laboratories Lactococcus lactis Lead Link Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Metastatic Melanoma Methodology Modeling Molecular Mucous Membrane Mus N-Acetylmuramoyl-L-alanine Amidase Oral Oral Administration Overdose Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pattern recognition receptor Peptides Peptidoglycan Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Positioning Attribute Probiotics Process Property Proteins Recombinants Refractory Renal carcinoma Research Signal Pathway Small Business Innovation Research Grant Solid Neoplasm Study models Toxicology Translations Validation Vancomycin resistant enterococcus Work anti-CTLA4 anti-CTLA4 antibodies anti-PD-L1 anti-PD-L1 therapy antitumor effect biomarker identification cancer immunotherapy cancer therapy cell bank cell type checkpoint therapy commensal bacteria commercialization cost drug development gut microbiome gut microbiota host microbiota improved in vivo innovation interest lactic acid bacteria lead candidate manufacturability manufacture microbial microbiome microbiota novel novel marker novel therapeutics patient response pre-clinical prevent product development programs research clinical testing response scale up synergism targeted agent therapeutic development tumor vaccine delivery

项目摘要

Project Summary The goal of this project is to develop a novel oral drug, R-5780, which engages microbiome-associated Pattern Recognition Receptors (PRRs) to enhance the activity of immune checkpoint inhibitor (ICI) therapy for the treatment of cancer. R-5780 is based on a unique enzyme known as secreted antigen A (SagA) identified from Enterococcus faecium which our research team showed can engage microbiome-associated immunological pathways of the gut and potentiate the effects of PD-1 and CTLA4 pathway targeting agents [19, 29, 30]. Gut microbiota are associated with remarkable effects on host health and disease, and discrete species of commensal bacteria have been correlated with improved patient responses to cancer immunotherapy [7-14]. The molecular mechanisms underlying these beneficial bacterial effects remain poorly understood. In particular, specific strains of Enterococci have been linked with improved response to anti-PD-1/PD-L1 treatment in patients with metastatic melanoma, lung, and kidney cancers, but their mechanism of action has not been elucidated nor employed to improve cancer immunotherapy. Recent work from our laboratory demonstrated that these beneficial strains of Enterococci express the SagA peptidoglycan remodeling enzyme which, when delivered recombinantly via a probiotic that does not endogenously express SagA, can potentiate the anti- tumor effects of PD-1 checkpoint therapy in murine tumor model studies. The peptidoglycan metabolites generated by SagA directly engage host PRRs activating key host immune signaling pathways [19]. While defined microbiome commensal strains may offer an interesting alternative to prevent and treat cancer in combination with ICI therapy, many strains are not suitable for human use (including certain SagA positive Enterococci), and the mechanism of action is difficult to characterize making drug development challenging. However, recent studies suggest that improved probiotics engineered to carry specific recombinant biological targeting agents to the gut can be an effective approach to target intestinal microbiome pathways. Indeed, our recent results demonstrate that engineering or ‘reprogramming’ of probiotics to recombinantly express and deliver SagA to the intestinal tract can impact immune responsiveness of cancer and greatly enhances the effects of ICI therapy. These anti-tumor effects occur via intestinal PRR engagement. Our goal is to develop a novel probiotic strain to deliver SagA (referred to as R-5780) as an orally administered drug that synergizes with ICI agents to enhance effectiveness of immunotherapy. The key objectives of are to: 1) finalize R-5780 validation by determining activity in a second tumor model, and demonstrating preliminary manufacturability, 2) perform necessary scale up process development to prepare for GMP manufacturing, 3) assess R-5780 activity in dose escalation studies and identify novel biomarkers that could be use in clinical trials, and 4) complete an IND-enabling GLP pharm tox study. Successful commercialization of R-5780 will profoundly advance immunotherapy treatment of cancer.

项目概要该项目的目标是开发一种新型口服药物 R-5780，它涉及微生物组相关模式识别受体（PRR）可增强免疫检查点抑制剂（ICI）治疗的活性 R-5780 的治疗基于一种称为分泌性抗原 A (SagA) 的独特酶。我们的研究小组证明，屎肠球菌可以参与微生物组相关的免疫学肠道通路并增强 PD-1 和 CTLA4 通路靶向药物的作用 [19,29,30]。肠道微生物群对宿主健康和疾病具有显着影响，并且不同的物种共生细菌与改善患者对癌症免疫治疗的反应相关[7-14]。这些有益细菌效应背后的分子机制仍然知之甚少。特定肠球菌菌株与抗 PD-1/PD-L1 治疗反应的改善有关转移性黑色素瘤、肺癌和肾癌患者，但其作用机制尚未明确我们实验室最近的工作表明，未阐明或用于改善癌症免疫治疗。这些有益的肠球菌菌株表达 SagA 肽聚糖重塑酶，当通过不内源表达 SagA 的益生菌重组递送，可以增强抗- PD-1 检查点疗法在小鼠肿瘤模型研究中的肿瘤效应。 SagA 产生的直接参与宿主 PRR 激活关键宿主免疫信号通路 [19]。虽然明确的微生物组共生菌株可能为预防和治疗癌症提供一种有趣的替代方案与ICI疗法联合使用时，许多菌株不适合人类使用（包括某些SagA阳性菌株）肠球菌），并且作用机制难以表征，这使得药物开发具有挑战性。然而，最近的研究表明，经过改造的益生菌可以携带特定的重组生物学事实上，针对肠道的靶向药物可能是针对肠道微生物组途径的有效方法。最近的结果表明，对益生菌进行工程或“重新编程”以重组表达和将 SagA 输送到肠道可以影响癌症的免疫反应并大大增强 ICI 疗法的效果是通过肠道 PRR 参与而产生的。新型益生菌菌株可递送 SagA（称为 R-5780）作为口服药物，具有协同作用与 ICI 药物一起增强免疫治疗的有效性主要目标是： 1) 最终确定 R-5780。通过确定第二个肿瘤模型中的活性并证明初步可制造性进行验证，2) 进行必要的放大工艺开发，为 GMP 生产做准备，3) 评估 R-5780 剂量递增研究中的活动并确定可用于临床试验的新型生物标志物，以及 4) 完成支持 IND 的 GLP 药物毒性研究。 R-5780的成功商业化将深刻推进癌症的免疫疗法。