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

BCCMA：改善晚期膀胱癌护理的转化研究

• 批准号: 10588312
• 负责人: CHONG-XIAN PAN
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588312
• 关键词: ARID1A gene; Abscopal effect; Animals; Attenuated; Autophagocytosis; Award; Basic Science; Bioinformatics; Bladder; Cancer Etiology; Caring; Cause of Death; Cell Culture Techniques; Cessation of life; Chemoresistance; Clinical; Clinical Trials; Combination Medication; Combination immunotherapy; Consultations; Cytotoxic Chemotherapy; Development; Diagnosis; Diagnostic; Disseminated Malignant Neoplasm; Fluorescence; Genes; Goals; Health; Home; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunotherapy; In Vitro; Intravenous; Intravenous infusion procedures; Legal patent; Licensing; Life; Light; Liver; Maintenance; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Medical; Medical Oncology; Modality; Modeling; Mus; Names; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Oral; Oral Administration; Organ; PIK3CG gene; PUVA Photochemotherapy; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Photosensitizing Agents; Plants; Prognosis; Proteins; Quality of life; Radical Cystectomy; Reactive Oxygen Species; Regimen; Research; Research Project Grants; Resistance; Safety; Salmonella; Secondary to; Services; Surface; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Translating; Translational Research; Treatment outcome; Tumor Immunity; United States Department of Agriculture; United States Food and Drug Administration; Urology; Veterans; Work; anti-cancer; cancer cell; cancer immunotherapy; cancer site; chemotherapy; comparative efficacy; cost; design; efficacy evaluation; efficacy study; immune activation; immune clearance; improved; in vivo; male; malignant mouth neoplasm; men; novel; oral immunotherapy; prevent; red fluorescent protein; response; systemic toxicity; targeted treatment; theranostics; tumor microenvironment; tumor-immune system interactions; vector vaccine

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.

该项目的副标题 开发针对晚期膀胱的口腔癌特异性四功能治疗诊断平台 癌症 概括 膀胱癌是男性第四大常见癌症，也是男性癌症死亡的第七大常见原因。 几乎所有膀胱癌死亡都是由晚期膀胱癌（aBC）引起的，这是本次研究的重点 项目。使用免疫检查点抑制剂（ICIs）的免疫疗法效果有限，且成本高昂， 通过静脉输注给药不方便，并且与显着的免疫介导相关 向非癌组织输送 ICI 并激活免疫反应后继发的毒性。这 该项目的目标是开发口腔癌特异性治疗诊断平台，该平台不仅可以为患者提供 ICI 具有药效增强、毒性降低、成本低廉、口服方便等优点，可用于治疗癌症部位。 也可用于光动力诊断和治疗。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传递到癌症部位，然后被光激活以发出红色 荧光用于光动力诊断，并产生用于光动力的活性氧（ROS） 治疗。沙门氏菌本身也可以改变和创造促免疫的肿瘤微环境（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- 癌症免疫力，同时消除与静脉免疫疗法相关的免疫介导的毒性。更多的 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 作用并增强疗效。该项目提出了四个具体目标。目标我是确定最 用于膀胱癌免疫治疗的有效的癌症特异性沙门氏菌治疗方案；目标 II 是确定是否 癌症特异性沙门氏菌可以根除局部晚期膀胱癌，诱导远隔效应，并且 预防癌症转移；目标三是确定作用和抵抗的根本机制；和 目标 IV 是确定癌症特异性沙门氏菌用于光动力诊断的潜力。 完成拟议工作后将与美国食品和药物管理局进行磋商 用于人类患者的临床试验。