STING agonist-expressing BCG for bladder cancer

摘要 每年有超过8万美国人被诊断出患有膀胱癌，超过1.7万人死于膀胱癌 疾病。约75%的新发膀胱癌患者存在非肌肉浸润性膀胱癌 (NMIBC)。NMIBC不仅与高复发率(50%)和进展风险有关，而且30%的 患者对标准的护理治疗无反应：经尿道膀胱内杆菌电切术 卡介苗(BCG)滴注，是唯一被批准的癌症微生物疗法。这些人被留了下来 治疗选择有限。虽然一直在努力产生改良的重组卡介苗(RBCG) 但是，与传统的卡介苗相比，这些努力尚未产生明显的改善。只有很少的 过去二十年来早期疾病的治疗进展和有限的治疗方法 在发展中，对改善NMIBC治疗的主要需求尚未得到满足。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，过度表达一种有效的刺激因子 干扰素基因(刺激性)激动剂。STING激动剂通过先天免疫增强抗肿瘤反应 STING-IRF3-NF-κB途径。而其他公司正在开发小分子刺痛激动剂作为新的 抗癌免疫疗法，OncoSTING是唯一一家通过 活细菌疫苗-卡介苗-本身就是一种众所周知的免疫疗法，已经在治疗中使用 对膀胱癌的治疗，因此提供了两者的好处。因为它是一种活细菌，OS-101允许 持续和长时间地将刺激剂输送到肿瘤微环境。与野性相比 BCG型OS-101在NMIBC模型中显示出优越的抗肿瘤效果；更强的促炎作用 细胞因子反应；更大的髓系细胞重新编程，产生M1移位 吞噬/自噬；关键细胞因子启动子区域更明显的表观遗传变化；以及 有利于抗肿瘤免疫的代谢变化。在这个快速通道项目的第一阶段，OncoSTING将创建 使用一种新的、正在申请专利的方法的下一代、无抗生素耐药性的0S-101版本。海流 RBCG原型OS-101依赖于使用抗生素耐药盒维持的细菌质粒。 然而，第三阶段的研究将需要移除抗生素耐药性基因。新技术的功效 构建，称为OS-151，然后将在四个相关的生物检测中得到确认。在第二阶段，将比较OS-151 对Adu-S100(目前正在进行临床试验的Aduro的小分子刺痛激动剂)和野生型卡介苗 膀胱癌相关模型的建立。还将进行OS-151的IND前、药代动力学和安全性研究 正在进行，优化工作将确保OS-151的规模化生产。最后，肿瘤重复给药 研究和再挑战研究将在小鼠同基因模型中进行。一旦获得批准，OS-151将首先 用于治疗对卡介苗无反应的NMIBC患者，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.