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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：
10258201
负责人：
Gary Fanger
金额：
$ 38.69万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258201
关键词：
Animals Antigens Bacteria Biological Biological Assay Biological Markers CTLA4 gene Cancer Patient Capital Cells 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 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 Small Business Innovation Research Grant Solid Neoplasm Study models Therapeutic Toxicology Translations Validation Vancomycin resistant enterococcus Work anti-CTLA4 anti-CTLA4 antibodies antitumor effect base biomarker identification cancer immunotherapy cancer therapy cell bank 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 patient response pre-clinical prevent product development programs research clinical testing response response biomarker scale up targeted agent 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.

项目总结