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.

该项目的子题 开发用于高级膀胱的口腔癌特异性Quadra功能疗法平台 癌症 概括 膀胱癌是男性癌症死亡的第四个最常见的癌症，也是第七最常见的癌症原因。 几乎所有膀胱癌死亡都是由晚期膀胱癌（ABC）引起的，这是重点 项目。免疫检查点抑制剂（ICI）的免疫疗法仅是中等有效的，昂贵的 不方便地通过静脉输注给药，并与明显的免疫介导 ICIS的毒性继发于对非癌组织的免疫反应的激活。这 该项目的目标是开发口腔特定的疗法平台，不仅可以为ICI提供ICI 功效增强，毒性降低，低成本和方便口服的癌症部位，但可以 也用于光动力诊断和治疗。在这个项目中，特定于癌症的衰减沙门氏菌 将特异性地向癌症部位传递蛋白质光敏剂，然后通过光激活以发出红色 光动力诊断的荧光，并产生活力的活性氧（ROS） 治疗。沙门氏菌本身还可以修改并创建促免疫肿瘤微环境（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 - 癌症免疫力，同时消除与静脉免疫疗法有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药 效果并增强功效。该项目提出了四个具体目标。目的我是确定最多的 有效的癌症特异性沙门氏菌方案用于膀胱癌免疫疗法； AIM 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，诱发潜入效应，并 预防癌症转移；目的III是确定作用和抵抗的潜在机制；和 目标IV是确定癌症特异性沙门氏菌对光动力诊断的潜力。 拟议工作的完成将导致与美国食品药品管理局进行磋商 用于人类患者的临床试验。