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

本项目副标题 口腔癌专用四功能晚期膀胱诊疗诊断平台的研制 癌 总结 膀胱癌是男性第四大常见癌症和第七大常见癌症死亡原因。 几乎所有的膀胱癌死亡都是由晚期膀胱癌（aBC）引起的，这是这方面的重点。 项目使用免疫检查点抑制剂（ICI）的免疫疗法仅是中等有效的，昂贵的， 通过静脉输注给药不方便，并与显著的免疫介导的 继发于向非癌组织递送ICI和激活针对非癌组织的免疫应答的毒性。的 该项目的目标是开发口腔癌特异性治疗诊断平台，不仅可以提供ICI， 具有增强的功效、降低的毒性、低成本和方便的口服给药，但可 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 将特异性地将蛋白质光敏剂递送到癌症部位，然后通过光激活以发射红色 用于光动力诊断的荧光，并产生用于光动力的活性氧簇（ROS） 疗法沙门氏菌本身也可以改变和创造促免疫肿瘤微环境（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，以激活抗肿瘤活性。 癌症免疫，同时消除与静脉内免疫疗法相关的免疫介导的毒性。更 重要是，光动力疗法、微生物疗法和免疫疗法可以实现协同抗癌 效果，提高疗效。本项目提出了四个具体目标。目的一是确定 膀胱癌免疫治疗的有效癌症特异性沙门氏菌方案;目的II是确定是否 该癌特异性沙门氏菌可根除局部晚期膀胱癌，诱导远位效应， 目的III是确定潜在的作用机制和耐药性;以及 目的四是确定潜在的癌症特异性沙门氏菌的光动力学诊断。 完成拟议的工作将导致与美国食品和药物管理局的磋商 用于人类患者的临床试验。

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.