INTRAVESICAL ONCOLYTIC THERAPY FOR BLADDER CANCER

项目摘要/摘要。 膀胱癌是美国主要的死亡原因，也是治疗费用最高的癌症。尽管如此， 目前只有一种新的膀胱癌治疗方法，即检查点抑制剂atezoluzimab，已在 过去的30年。溶瘤病毒是一种有选择性地感染和杀死癌细胞的病毒，是一种强有力的新型 通过病毒诱导的直接杀伤和强大的免疫激活来介导抗癌活性的免疫疗法 对肿瘤相关抗原的反应。Vyriad的铅溶瘤麻疹病毒产品MV-NIS已经 静脉和腹膜外治疗晚期肺癌的临床安全性和有效性 分别为多发性骨髓瘤和卵巢癌，并在体外研究中有效地杀死膀胱癌细胞系。 我们的目标是开发溶瘤MV-NIS作为治疗膀胱癌的新方法，膀胱癌是一种 表现出对免疫治疗的敏感性。大多数患者被诊断为非肌肉侵袭性疾病。 疾病(NMIBC)，其中约50%的患者未能通过一线治疗。这些病人，还有病人 患有肌肉侵袭性疾病(MIBC)，没有有效的治疗选择，面临疾病的可能性 进展或转移，通常接受根治性膀胱切除术(完全膀胱切除)，这对 影响生活质量。在此SBIR快速通道应用中，我们建议：(I)确认可行性并确定 MV-NIS膀胱内给药的最佳条件和(Ii)进行一期临床试验以评估 根治性膀胱切除术患者的膀胱内MV-NIS治疗。这项研究将提供 对MV-NIS膀胱内给药的可行性和安全性的关键论证，以及初步 在一项关键的临床试验中，为推进MV-NIS治疗的决定提供治疗效果的迹象 寻求批准作为一种新的膀胱癌治疗方法。我们利用一种创新的临床试验设计，允许 包括抗肿瘤特性在内的MV-NIS治疗作用机制的相关分析 免疫反应。这将为未来的研究提供信息，将MV-NIS治疗与批准的检查点相结合 抑制剂有可能为局部晚期或慢性阻塞性肺疾病患者开发更有效的治疗方法 转移性膀胱癌。我们正在把Vyriad的团队聚集在一起，他们是溶瘤病毒治疗的领先专家 与梅奥诊所全国排名第一的泌尿科合作开展这项研究 如果成功，将导致批准一种新的、急需的膀胱癌治疗方法。

PROJECT SUMMARY/ABSTRACT . Bladder cancer is a leading cause of death in the US and the most expensive cancer to treat. Despite this, there has been only one new bladder cancer therapy, the checkpoint inhibitor atezoluzimab, approved in the past 30 years. Oncolytic viruses, viruses that selectively infect and kill cancer cells, are a potent new class of immunotherapy that mediate anticancer activity by direct virus induced killing and robust activation of immune responses against tumor associated antigens. Vyriad's lead oncolytic measles virus product, MV-NIS, has shown clinical safety and efficacy following intravenous and intraperitoneal treatment in patients with advanced multiple myeloma and ovarian cancer respectively and potently kills bladder cancer cell lines in in vitro studies. Our goal is to develop oncolytic MV-NIS as a new treatment for bladder cancer, a malignancy that has demonstrated susceptibility to immunotherapy. A majority of patients are diagnosed with non-muscle invasive disease (NMIBC), of which approximately 50% of patients fail first line therapy. These patients, and patients with muscle invasive disease (MIBC), have no effective therapeutic options and facing the likelihood of disease progression or metastasis,often undergo radical cystectomy (complete bladder removal) which significantly impacts quality of life. In this SBIR fast-track application we propose to (I) confirm feasibility and identify optimal conditions for intravesical administration of MV-NIS and (II) carry out a Phase 1 clinical trial to evaluate intravesical MV-NIS therapy in patients scheduled to undergo radical cystectomy. This study will provide the critical demonstration of feasibility and safety of intravesical MV-NIS administration, as well preliminary indication of therapeutic efficacy to inform the decision to advance MV-NIS therapy in a pivotal clinical trial to seek approval as a novel bladder cancer therapy. We utilize an innovative clinical trial design that allows correlative analysis to define mechanism of action of MV-NIS therapy including characterization of antitumor immune responses. This will inform future studies to combine MV-NIS therapy with approved checkpoint inhibitors to potentially develop a more potent therapeutic approach for patients with locally advanced or metastatic bladder cancer. We are bringing together Vyriad's team, leading experts in oncolytic virotherapy development, with Mayo Clinic's nationally number one ranked Urology department, to perform this study that will, if successful, lead to the approval of a new, much-needed treatment for bladder cancer patients.