Immunotherapy of human bladder cancer

人类膀胱癌的免疫治疗

基本信息

批准号：
9514095
负责人：
Lawrence Fong
金额：
$ 36.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-02 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514095
关键词：
Antibodies Antibody Therapy Antigens Antitumor Response BCG Live Biological Markers Biopsy Bladder Bladder Neoplasm Blood Blood Circulation Cancer Patient Cell physiology Cells Cisplatin Clinical Clinical Research Clinical Trials Clone Cells Comorbidity Correlative Study Cystectomy Data Disease Drug Targeting Effectiveness Flow Cytometry Future Human Immune Immune response Immunity Immunologics Immunology procedure Immunotherapeutic agent Immunotherapy In complete remission Individual Infiltration Laboratory Finding Localized Disease Malignant Neoplasms Malignant neoplasm of urinary bladder Modality Muscle Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Organ Outcome PDCD1LG1 gene Pathologic Patients Phase Phase I Clinical Trials Phase II Clinical Trials Proteins Radical Cystectomy Recurrence Refractory Resected Retreatment Role SLEB2 gene Salvage Therapy San Francisco Site Surface T-Cell Receptor T-Lymphocyte Tissues Toxic effect Transitional Cell Carcinoma Treatment-related toxicity Tumor Tissue Work adaptive immune response anti-tumor immune response base bladder transitional cell carcinoma cancer therapy chemotherapy circulating biomarkers density design high throughput screening immune activation immune checkpoint blockade immunoregulation improved intravesical malignant breast neoplasm next generation sequencing novel novel therapeutics predicting response predictive marker prevent public health relevance receptor recruit relapse patients response standard of care therapy development treatment effect treatment response tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Immunotherapy has emerged as an important treatment modality for cancer. In contrast to most other cancer treatments, immunotherapy can induce durable clinical response in metastatic disease. Antibodies targeting PD-1 and anti-PD-L1 have shown significant clinical activity in multiple diseases. Importantly, dramatic clinical responses have been seen in patients with the metastatic bladder, a disease in which no new drugs have been approved for over 20 years. The mechanism by which these immunotherapies work in cancer patients is unknown, nor are there robust biomarkers that predict of response to these treatments. We will perform a clinical study administering anti-PD-L1 antibody in patients with localized bladder cancer prior to these patients undergoing planned surgery for their cancer. We propose to study the effects of anti-PD-L1 antibody treatment not just in the blood but within the actual tumor. We will determine whether this immunotherapy increases the number of T cells into the tumor by examining tissues from biopsies obtained before treatment and from the bladder tumor resected following treatment. We will use next generation sequencing to track individual T cell clones in the blood and tumors to also determine whether T cells present in the tumor are being recruited to the tumor site or were already at the tumor. We will study how this treatment activates a systemic immune response. Understanding how these treatments work within patients, including at the level of the tumor tissue, will provide avenues t improve the efficacy of this approach and/or develop biomarkers to identify those patients that can benefit from treatment. Moreover, if significant tumor regression is seen, this treatment approach could transform our approach to localized bladder cancer. Finally, the clinical and laboratory findings derived from this trial may also help transform in how metastatic bladder cancer could be treated and contribute significantly to the design of future clinical trials with P-L1 and/or PD-1 targeted drugs.

描述（由申请人提供）：免疫疗法已成为癌症的重要治疗方式，与大多数其他癌症治疗相比，免疫疗法可以在转移性疾病中诱导持久的临床反应。重要的是，在转移性膀胱患者中观察到了显着的临床反应，这种疾病已经有 20 多年没有新药获得批准。这些免疫疗法在癌症患者中发挥作用的机制。尚不清楚，也没有强有力的生物标志物来预测对这些治疗的反应，我们将在局部膀胱癌患者接受计划的癌症手术之前进行一项临床研究。抗 PD-L1 抗体治疗不仅在血液中，而且在实际肿瘤内的效果我们将通过检查治疗前获得的活检组织和切除的膀胱肿瘤来确定这种免疫疗法是否增加进入肿瘤的 T 细胞数量。我们将使用下一代治疗。通过测序来追踪血液和肿瘤中的单个 T 细胞克隆，以确定肿瘤中存在的 T 细胞是否被招募到肿瘤部位或已经存在于肿瘤中。我们将研究这种治疗如何激活全身免疫反应。这些治疗在患者体内发挥作用，包括在肿瘤组织水平上，将为提高这种方法的功效和/或开发生物标志物来识别那些可以从治疗中受益的患者提供途径。治疗方法可以改变我们治疗局部膀胱的方法最后，该试验的临床和实验室结果也可能有助于改变转移性膀胱癌的治疗方式，并为未来 P-L1 和/或 PD-1 靶向药物的临床试验设计做出重大贡献。