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.

抽象的每年有超过 80,000 名美国人被诊断患有膀胱癌，超过 17,000 人死于膀胱癌大约 75% 的新发膀胱癌患者患有非肌层浸润性膀胱癌。 (NMIBC) 不仅与高复发率 (>50%) 和进展风险相关，而且与 30% 的复发率相关。患者对标准护理治疗无反应：膀胱内注射芽孢杆菌经尿道切除术卡介苗（BCG）滴注是唯一被批准的癌症微生物疗法。虽然治疗选择有限，但人们一直在努力生产改良的重组卡介苗（rBCG）。但与传统卡介苗相比，这些努力尚未取得明显的改善。过去二十年早期疾病治疗的进展和有限的治疗方案在开发过程中，对于改进 NMIBC 的治疗方法存在重大未满足的需求。 OncoSTING 正在开发 OS-101，这是一种突破性的 rBCG 免疫疗法，可过度表达有效的刺激物 IFN 基因 (STING) 激动剂通过先天免疫增强抗肿瘤反应。而其他公司正在开发新的小分子 STING 激动剂。 OncoSTING 是唯一一家开发 STING 激动剂递送的公司活细菌疫苗（BCG）本身就是一种众所周知的免疫疗法，已用于治疗 OS-101 是一种活细菌，因此具有两者的优点。与野生状态相比，STING 激动剂持续且长时间地递送至肿瘤微环境。 BCG 型 OS-101 在 NMIBC 模型中表现出卓越的抗肿瘤功效；细胞因子反应；更大的骨髓细胞重编程，产生增强的 M1 转变吞噬作用/自噬；关键细胞因子启动子区域更明显的表观遗传变化；在该快速通道项目的第一阶段，OncoSTING 将创建有利于抗肿瘤免疫的代谢组学变化。 0S-101 的下一代无抗生素耐药性版本，采用了一种正在申请专利的新颖方法。 rBCG 原型 OS-101 依赖于使用抗生素抗性盒维持的细菌质粒。然而，第 3 期研究将需要去除抗生素抗性基因来验证新药的功效。然后，将在四项相关的生物测定中对 OS-151 进行确认。在第二阶段，将对 OS-151 进行比较。 ADU-S100（Aduro 的小分子 STING 激动剂，目前正在进行临床试验）和野生型 BCG OS-151的Pre-IND、药代动力学和安全性研究也将进行。进行的优化工作将确保 OS-151 的大规模生产。最后，重复肿瘤给药。一旦获得批准，OS-151将首先在小鼠同系模型中进行研究和再挑战研究。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。