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：
10596291
负责人：
Gary Fanger
金额：
$ 104.97万
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/10596291
关键词：
Animals Antigens Bacteria Biological Biological Assay Biological Markers CTLA4 gene Cancer Patient Capital Clinical Clinical Research Clinical Trials DNA cassette Development Disease Dose Drug Kinetics 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 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 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 antitumor effect base biomarker identification cancer immunotherapy cancer therapy cell bank cell type checkpoint therapy commensal bacteria commercialization cost drug development drug mechanism gut microbiome gut microbiota host microbiota improved in vivo innovation interest lactic acid bacteria lead candidate manufacturability microbial microbiome microbiota novel novel marker novel therapeutics patient response pre-clinical prevent product development programs research clinical testing response response biomarker scale up 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.

项目摘要该项目的目的是开发一种新型的口服药物R-5780，该药物与微生物组相关的模式参与识别受体（PRR）以增强免疫粘液抑制剂（ICI）治疗的活性癌症的治疗。 R-5780基于一种独特的酶，称为分泌的抗原A（Saga）我们的研究小组表明的肠球菌可以参与微生物组相关的免疫学肠道的途径和潜在的PD-1和CTLA4途径靶向剂的影响[19，29，30]。肠道微生物群对宿主健康和疾病的显着影响以及离散的物种有关共生细菌与改善患者对癌症免疫疗法的反应相关[7-14]。这些有益细菌效应的分子机制仍然鲜为人知。尤其，肠球菌的特定菌株与对抗PD-1/PD-L1处理的反应有关转移性黑色素瘤，肺和肾脏癌的患者，但其作用机理并非阐明或用于改善癌症免疫疗法。我们实验室的最新工作证明了这些有益的肠球菌菌株表达了saga pepperydoglycan重塑酶通过不发表内源性传奇的益生菌进行重组，可以潜在 PD-1检查点疗法在鼠肿瘤模型研究中的肿瘤作用。辣椒粉代谢产物 SAGA生成的直接使宿主PRRS激活关键主机免疫信号通路[19]。虽然定义的微生物组分子菌株可能会提供一种有趣的替代方法，以预防和治疗癌症与ICI治疗相结合，许多菌株不适合人类使用（包括某些传奇阳性肠球菌），作用机理很难表征使药物开发挑战的表征。但是，最近的研究表明，改进的益生菌已设计为携带特定重组生物学将剂量靶向肠道可能是靶向肠道微生物组途径的有效方法。确实，我们的最近的结果表明，工程或“重编程”益生菌重组表达和向肠道传递传奇可以影响癌症的免疫反应性，并大大提高 ICI疗法的影响。这些抗肿瘤作用通过肠道PRR参与而发生。我们的目标是开发新颖的益生菌菌株传递传送（称为R-5780）作为一种口服的药物，以协同作用使用ICI药物增强免疫疗法的有效性。关键对象是：1）最终确定R-5780 通过确定第二个肿瘤模型中的活动并证明初步制造的验证，2）进行必要的规模开发以准备GMP制造，3）评估R-5780 剂量升级研究的活性并鉴定可用于临床试验的新型生物标志物，4）完成一项辅助GLP Pharm Tox研究。 R-5780的成功商业化将深刻地促进对癌症的免疫疗法治疗。