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

• 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
• 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

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 该项目的目标是开发一种新型口服药物R-5780，它与微生物组相关的模式 识别受体（PRR），以增强免疫检查点抑制剂（ICI）治疗的活性， 癌症的治疗。R-5780是基于一种独特的酶，称为分泌抗原A（佐贺），从 我们的研究小组发现，屎肠球菌可以参与微生物组相关的免疫反应， 因此，本发明的药物组合物可增强肠道的PD-1和CTLA 4通路的靶向剂的作用[19，29，30]。 肠道微生物群与对宿主健康和疾病的显著影响有关，并且肠道微生物群的离散物种 肠道细菌与改善患者对癌症免疫治疗的反应相关[7-14]。的 这些有益细菌作用的分子机制仍然知之甚少。特别是， 肠球菌的特定菌株与抗PD-1/PD-L1治疗的应答改善有关， 转移性黑色素瘤、肺癌和肾癌患者，但其作用机制尚不清楚。 也不用于改善癌症免疫疗法。我们实验室最近的工作表明， 这些有益的肠球菌菌株表达佐贺肽聚糖重塑酶， 通过不内源性表达佐贺的益生菌重组递送，可以增强抗- PD-1检查点疗法在鼠肿瘤模型研究中的肿瘤效应。肽聚糖代谢物 由佐贺产生的抗体直接接合宿主PRR，激活关键的宿主免疫信号传导途径[19]。 虽然确定的微生物组菌株可能提供一种有趣的替代方案来预防和治疗癌症， 与ICI疗法组合，许多菌株不适合人类使用（包括某些佐贺阳性菌株）。 肠球菌），并且作用机制难以表征，使得药物开发具有挑战性。 然而，最近的研究表明，改良的益生菌工程携带特定的重组生物， 将药剂靶向肠道可以是靶向肠道微生物组途径的有效方法。的确，我们的 最近的结果表明，工程化或“重编程”益生菌以重组表达和 将佐贺输送到肠道可以影响癌症的免疫反应并大大增强免疫反应。 ICI治疗的效果。这些抗肿瘤作用通过肠道PRR参与发生。我们的目标是发展一个 一种新型益生菌菌株，其作为口服给药药物递送佐贺（称为R-5780）， 与ICI试剂一起使用以增强免疫疗法的有效性。主要目标是：1）完成R-5780 通过测定第二肿瘤模型中的活性并证明初步可制造性进行验证，2） 进行必要的规模放大工艺开发，为GMP生产做准备，3）评估R-5780 在剂量递增研究中的活性，并鉴定可用于临床试验的新生物标志物，以及4） 完成IND启动GLP药物毒性研究。 R-5780的成功商业化将大大推进癌症的免疫治疗。