Immunotherapy of human bladder cancer

 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反，免疫疗法可以在转移性疾病中诱导持久的临床反应。靶向PD-1和抗PD-L1的抗体已在多种疾病中显示出显著的临床活性。重要的是，在转移性膀胱患者中观察到了戏剧性的临床反应，这种疾病在20多年来没有新药被批准。这些免疫疗法在癌症患者中起作用的机制尚不清楚，也没有可靠的生物标志物来预测对这些治疗的反应。 我们将进行一项临床研究，在局部膀胱癌患者接受计划的癌症手术前，给予这些患者抗PD-L1抗体。我们建议研究抗PD-L1抗体治疗不仅在血液中，而且在实际肿瘤中的作用。我们将通过检查治疗前获得的活检组织和治疗后切除的膀胱肿瘤组织来确定这种免疫疗法是否增加了进入肿瘤的T细胞数量。我们将使用下一代测序来跟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细胞是否正在被招募到肿瘤部位或已经在肿瘤中。我们将研究这种治疗如何激活全身免疫反应。 了解这些治疗如何在患者体内起作用，包括在肿瘤组织水平，将提供提高这种方法的疗效和/或开发生物标志物的途径，以识别那些可以从治疗中受益的患者。此外，如果观察到显著的肿瘤消退，这种治疗方法可能会改变我们对局部膀胱癌的治疗方法。最后，来自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。

 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.