BCCMA: Translational research to improve the care of advanced bladder cancer

本项目副标题 口腔癌四功能晚期膀胱腔内治疗平台的研制 癌症 摘要 膀胱癌是男性第四种最常见的癌症，也是导致癌症死亡的第七大常见原因。 几乎所有的膀胱癌死亡都是由晚期膀胱癌(Abc)引起的，这是本研究的重点。 项目。使用免疫检查点抑制剂(ICIS)的免疫疗法只是中等有效、昂贵、 不方便地通过静脉输液给药，并与显著的免疫介导相关 ICIS对非癌组织的传递和对非癌组织的免疫反应的激活引起的继发性毒性。这个 该项目的目标是开发针对口腔癌的治疗平台，不仅可以将ICI传递到 具有增强疗效、降低毒性、低成本和方便口服的癌症部位，但可以 也可用于光动力学诊断和治疗。在这个项目中，癌症特异性减毒沙门氏菌 会专门将一种蛋白质光敏剂输送到癌症部位，然后被光激活发出红色 用于光动力诊断的荧光，并产生用于光动力的活性氧(ROS) 心理治疗。沙门氏菌本身也可以改变和创造有利于免疫的肿瘤微环境(微生物疗法)。 此外，癌症特异性沙门氏菌可以在癌症部位局部表达ICI，以激活抗 癌症免疫，同时消除与静脉免疫治疗相关的免疫介导性毒性。更多 重要的是，光动力疗法、微生物疗法和免疫疗法可以实现协同抗癌。 发挥功效，增强疗效。本项目提出了四个具体目标。我的目标是确定最多的 有效的癌症特异性沙门氏菌方案用于膀胱癌免疫治疗；目的II是确定 癌症特异性沙门氏菌可以根除局部晚期膀胱癌，产生非局部性效应，以及 预防癌症转移；目标三是确定潜在的作用和耐药机制；以及 目的四是确定癌症特异性沙门氏菌用于光动力学诊断的潜力。 拟议工作的完成将导致与美国食品和药物管理局的磋商 在人类病人身上进行临床试验。

Sub-Title of This Project Development of an oral cancer-specific quadra-functional theranostic platform for advanced bladder cancer SUMMARY Bladder cancer is the fourth most common cancer and seventh most common cause of cancer death in men. Almost all bladder cancer deaths are caused by advanced bladder cancer (aBC) which is the focus of this project. Immunotherapy with immune checkpoint inhibitors (ICIs) is only moderately effective, costly, inconveniently administrated through intravenous infusion and associated with significant immune-mediated toxicity secondary to delivery of ICIs to and activation of immune response against non-cancerous tissues. The goal of this project is to develop oral cancer-specific theranostic platform that can not only deliver an ICI to cancer sites with enhanced efficacy, decreased toxicity, low cost and convenient oral administration, but can also be used for photodynamic diagnosis and therapy. In this project, cancer-specific attenuated Salmonella will specifically deliver a protein photosensitizer to cancer sites which is then activated by light to emit red fluorescence for photodynamic diagnosis, and to produce reactive oxygen species (ROS) for photodynamic therapy. Salmonella itself can also modify and create pro-immune tumor microenvironment (microbiotherapy). Furthermore, the cancer-specific Salmonella can express an ICI locally at the cancer sites to activate anti- cancer immunity while eliminating immune-mediated toxicity associated with intravenous immunotherapy. More importantly, photodynamic therapy, microbiotherapy and immunotherapy can achieve synergistic anti-cancer effects and enhance the efficacy. Four specific aims are proposed in this project. Aim I is to determine the most effective cancer-specific Salmonella regimen for bladder cancer immunotherapy; Aim II is to determine whether the cancer-specific Salmonella can eradicate locally advanced bladder cancer, induce abscopal effect, and prevent cancer metastasis; Aim III is to determine the underlying mechanisms of action and resistance; and Aim IV is to determine the potential of the cancer-specific Salmonella for photodynamic diagnosis. Accomplishment of the proposed work will lead to the consultation with the US Food and Drug Administration for clinical trials in human patients.