STING agonist-expressing BCG for bladder cancer

摘要 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。 疾病大约75%的新膀胱癌患者表现为非肌层浸润性膀胱癌 （NMIBC）。NMIBC不仅与高复发率（>50%）和进展风险相关， 患者对标准护理治疗无反应：膀胱内芽孢杆菌经尿道切除术 Calmette-Guérin（BCG）滴注，唯一获批的癌症微生物治疗剂。这些人只剩下 治疗选择有限虽然已经努力产生改进的重组BCG（rBCG）， 菌株，这些努力尚未取得明显的改善，传统的BCG。除了极少数 在过去二十年中，早期疾病的治疗取得了进展， 在开发中，对于NMIBC的改进治疗存在主要的未满足的需求。为了满足这一需求， Oncosting正在开发OS-101，这是一种突破性的rBCG免疫疗法，可过表达一种有效的刺激剂 IFN基因（STING）激动剂。STING激动剂通过先天免疫增强抗肿瘤应答 STING-IRF 3-NF-κB通路。虽然其他公司正在开发小分子STING激动剂作为新的 抗癌免疫疗法，Oncosting是唯一一家开发STING激动剂递送的公司， 活细菌疫苗-BCG-本身是一种众所周知的免疫疗法，已用于治疗 膀胱癌，因此提供了两者的好处。因为它是一种活细菌，OS-101允许 STING激动剂向肿瘤微环境的连续和延长的递送。比野生 型BCG，OS-101在NMIBC模型中表现出上级抗肿瘤功效;更有效的促炎性 细胞因子反应;更大的骨髓细胞重编程，产生M1移位， 关键细胞因子启动子区域中更明显的表观遗传变化;以及 有利于抗肿瘤免疫的代谢组学变化。在这个快速通道项目的第一阶段，Oncosting将创建 下一代，抗生素耐药性的版本0 S-101使用一种新的，正在申请专利的方法。当前 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，3期研究将需要去除抗生素耐药基因。新产品的功效 构建体，称为OS-151，然后将在四个相关的生物测定中确认。在第二阶段，将比较OS-151 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， 膀胱癌的相关模型。还将开展OS-151的IND前、药代动力学和安全性研究。 优化工作将确保OS-151的大规模生产。最后，肿瘤重复给药 研究和再激发研究将在小鼠同系模型中进行。一旦获得批准，OS-151将首先 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。

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.