STING agonist-expressing BCG for bladder cancer

表达 STING 激动剂的 BCG 用于治疗膀胱癌

基本信息

批准号：
10668536
负责人：
Todd Wallach
金额：
$ 109.3万
依托单位：
ONCOSTING 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：
2021-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10668536
关键词：
Address Agonist American Animals Antibiotic Resistance Antibiotics Antitumor Response Attenuated Vaccines Autophagocytosis BCG Live Bacillus Calmette-Guerin Therapy Bacteremia Bacteria Bacterial Vaccines Biological Assay COVID-19 Cancer Patient Carcinoma in Situ Cell Reprogramming Cells Cessation of life Clinical Research Clinical Trials Complement DNA cassette Data Development Diagnosis Disease Dose Drug Kinetics Effectiveness Ensure Epigenetic Process Equation Excision Fermentation Generations Genes Genetic Growth IRF3 gene Immune Immunity Immunotherapy In Vitro Individual Infection Inflammatory Inflammatory Response Pathway Interferons Left Legal patent Light Liquid substance Macrophage Malignant Neoplasms Malignant neoplasm of urinary bladder Methods Modeling Mucous Membrane Mus Myeloid Cells Newly Diagnosed Pantothenic Acid Pathway interactions Patients Phagocytosis Phase Phenotype Plasmids Positioning Attribute Preparation Production Promoter Regions Recombinants Recurrence Recurrent disease Relapse Resistance Resources Reverse Transcriptase Polymerase Chain Reaction Safety Standardization Stimulator of Interferon Genes Submucosa Therapeutic Time Training Transurethral Resection Treatment Cost Tumor Immunity Viral Physiology Work anti-tumor immune response antitumor effect auxotrophy cancer immunotherapy clinical efficacy cytokine effector T cell head-to-head comparison improved intravesical manufacture men metabolomics microbial microorganism next generation non-muscle invasive bladder cancer novel novel therapeutics overexpression phase 3 study prevent progression risk prototype recruit resistance gene safety study small molecule standard of care success tumor tumor eradication tumor microenvironment

项目摘要

Abstract More than 80,000 Americans are diagnosed with bladder cancer each year, and more than 17,000 die from the disease. Approximately 75% of new bladder cancer patients present with non-muscle invasive bladder cancer (NMIBC). Not only is NMIBC associated with high recurrence rates (>50%) and risk of progression, but 30% of patients are unresponsive to the standard of care treatment: transurethral resection with intravesical Bacillus Calmette-Guérin (BCG) instillation, the only approved microbial therapeutic for cancer. These individuals are left with limited therapeutic options. While there have been efforts to generate improved recombinant BCG (rBCG) strains, such efforts have not yet yielded demonstrable improvement over traditional BCG. With very few advances in treatment over the past two decades for early stage disease and a limited pipeline of therapeutics in development, there is a major unmet need for improved treatments for NMIBC. To address this need, OncoSTING is developing OS-101, a breakthrough rBCG immunotherapy that overexpresses a potent Stimulator of IFN Genes (STING) agonist. STING agonists potentiate anti-tumor responses through the innate immune STING-IRF3-NF-κB pathway. While other companies are developing small molecule STING agonists as novel anti-cancer immunotherapies, OncoSTING is the only company developing STING agonist delivery by a live bacterial vaccine—BCG—that itself is a well-known immunotherapy already in use for the treatment of bladder cancer, thus offering the benefits of both. Because it is a live bacteria, OS-101 allows for continuous and prolonged delivery of the STING agonist to the tumor microenvironment. Compared with wild type BCG, OS-101 demonstrates superior antitumor efficacy in models of NMIBC; more potent pro-inflammatory cytokine responses; greater myeloid cell reprogramming, producing an M1 shift with enhanced phagocytosis/autophagy; more pronounced epigenetic changes in key cytokine promoter regions; and metabolomic changes favoring antitumor immunity. In Phase I of this Fast Track project, OncoSTING will create a next-generation, antibiotic resistance-free version of 0S-101 using a novel, patent-pending method. The current rBCG prototype, OS-101, relies on a bacterial plasmid that is maintained using an antibiotic resistance cassette. However, Phase 3 studies will require the removal of antibiotic resistance genes. The efficacy of the new construct, called OS-151, will then be confirmed in four relevant bioassays. In Phase II, OS-151 will be compared to ADU-S100 (Aduro's small molecule STING agonist which is in current clinical trials) and wild type BCG in relevant models of bladder cancer. Pre-IND, pharmacokinetic and safety studies of OS-151 will also be conducted, and optimization work will ensure production of OS-151 at scale. Finally, tumor repetitive dosing studies and rechallenge studies will be carried out in mouse syngeneic models. Once approved, OS-151 will first be used to treat patients with BCG-unresponsive NMIBC, with potential to expand to other cancer indications.

抽象的每年有80,000多名美国人被诊断出患有膀胱癌，并死于17,000多名疾病。大约75％的新膀胱癌患者出现了非肌肉浸润性膀胱癌（NMIBC）。 NMIBC不仅与高复发率（> 50％）和进展风险相关联，而且有30％患者对护理水平治疗的标准没有反应：静脉切除术中静脉内切除术 Calmette-Guérin（BCG）灌输是唯一认可的癌症的微生物疗法。这些人留下有限的治疗选择。尽管已经努力产生改进的重组BCG（RBCG）与传统BCG相比，这种努力尚未产生明显的改善。很少在过去的二十年中，早期疾病的治疗进展和治疗方案有限在开发中，对NMIBC的治疗方法有很大的未满足。为了满足这种需求， Oncosting正在开发OS-101，这是一种突破性的RBCG免疫疗法，过表达潜在的刺激剂 IFN基因（sting）激动剂的作用。通过先天免疫来刺痛激动剂潜在的抗肿瘤反应 Sting-IRF3-NF-κB途径。而其他公司正在开发小分子刺痛动力学家作为新颖抗癌免疫疗法，OnoSosting是唯一通过活细菌疫苗（BCG）本身是一种已用于治疗的众所周知的免疫疗法膀胱癌，因此提供两者的好处。因为它是活细菌，所以OS-101允许刺痛激动剂的连续和长时间递送到肿瘤微环境。与野生相比 BCG型，OS-101在NMIBC模型中表现出优异的抗肿瘤效率。更多潜在的促炎细胞因子反应；更大的髓样细胞重编程，产生M1转移，并增强吞噬作用/自噬；关键细胞因子启动子区域中更明显的表观遗传变化；和代谢组变化有利于抗肿瘤免疫。在这个快速轨道项目的第一阶段中，打击将创建使用一种新颖的，申请专利的方法，是0s-101的下一代，无抗生素抗性版本。电流 RBCG原型OS-101依赖于使用抗生素耐药性盒保持的细菌质粒。但是，第3阶段的研究将需要去除抗生素耐药性基因。新的效率然后将在四个相关的生物测定中确认构造，称为OS-151。在第二阶段，将比较OS-151 到ADU-S100（在当前的临床试验中，Aduro的小分子刺痛激动剂）和野生型BCG 膀胱癌的相关模型。 OS-151的预先指示，药代动力学和安全性研究也将是进行的，优化工作将确保大规模生产OS-151。最后，肿瘤重复剂量研究和补偿研究将在小鼠同步模型中进行。一旦获得批准，OS-151将首先可用于治疗BCG无反应的NMIBC患者，并有可能扩展到其他癌症适应症。