Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

定义肿瘤内形态、免疫和突变异质性对尿路上皮癌的影响

• 批准号: 10337035
• 负责人: Hikmat Al-Ahmadie
• 金额: $ 40.26万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337035
• 关键词: Address; Antibodies; Area; Biological; Biological Markers; CD8B1 gene; Cancer Patient; Clinical; Clinical Trials; Clonality; Collection; Combined Modality Therapy; Data; Development; Disease; Disease Progression; Disease Resistance; Distant Metastasis; Drug resistance; Evaluation; Exhibits; FDA approved; Foxes; Genetic; Genomics; Goals; Heterogeneity; Histologic; Histology; Imaging technology; Immune; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunogenomics; Immunohistochemistry; Immunologic Markers; Immunologics; Immunotherapy; In complete remission; Individual; Investigation; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Minority; Morphology; Multiplexed Ion Beam Imaging; Muscle; Mutation; PDL1 inhibitors; PTPRC gene; Patients; Phenotype; Preparation; Prevalence; Primary Neoplasm; Resistance; Role; Sampling; Slide; Source; Squamous Differentiation; T-Lymphocyte; Therapeutic; Time; Tissues; Transitional Cell Carcinoma; Treatment Failure; Treatment outcome; Tumor-infiltrating immune cells; Urothelium; Variant; anti-PD-1; anti-PD-L1; base; bladder transitional cell carcinoma; cancer cell; checkpoint therapy; cohort; combinatorial; exome; exome sequencing; genomic profiles; immune checkpoint blockade; immunogenic; improved; insight; men; molecular subtypes; neoantigens; patient response; predicting response; prevent; programmed cell death ligand 1; receptor; response; standard care; transcriptome; transcriptome sequencing; treatment response; tumor; tumor heterogeneity; tumor progression

Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma Bladder cancer is the ninth most common cancer worldwide and the fourth most common cancer in men. Despite intensive multi-modality therapy, approximately 50% of patients with muscle-invasive disease develop distant metastases and historically such patients had little hope of long-term survival. The development of immune checkpoint inhibitors is the most significant therapeutic advance in bladder cancer in three decades and the development of these agents have provided renewed hope to many patients with previously incurable metastatic disease. Anti-PD1/PD-L1 antibodies can induce durable complete responses in patients with metastatic bladder cancer with several immune checkpoint inhibitors are now FDA-approved for this indication. However, the majority of patients with metastatic urothelial cancers do not benefit from immune checkpoint blockade and some patients who initially respond later develop acquired resistance. The biologic basis for innate and acquired resistance to immune checkpoint blockade in urothelial cancer remains poorly defined. Urothelial cancers display a wide spectrum of variant morphologies that often co-exist within individual tumors. We have shown that this morphologic heterogeneity is often associated with intra-tumoral mutational heterogeneity. The current proposal is based upon preliminary data indicating that morphologic heterogeneity in bladder cancer is associated with genomic and immune heterogeneity and is predictive of a worse response to atezolizumab (an anti-PD-L1 inhibitor). Three aims are proposed. In Aim 1, we will perform integrated histologic, genomic and immune analyses of paired, macro-dissected, morphologically distinct areas from morphologically heterogeneous tumors from patients treated with immune checkpoint blockade to define the prevalence and extent of intratumoral genetic and immune heterogeneity. In Aim 2, these tissue profiling studies will be integrated with detailed clinical and patients response data to define the role of pre-existent histologic, genomic and immune heterogeneity in determining response to systemic immunotherapy. Finally, in Aim 3, we will study tumors collected at the time of disease progression in patients treated with immune checkpoint inhibitors to determine whether pre-existent drug resistant clones were present in morphologically heterogeneous primary tumors and that these less immunogenic cancer cells are a basis for drug resistance and disease progression in patients with morphologically heterogeneous tumors. The long-term translational objective will be to use the biologic insights gained to develop improved biomarkers of immunotherapy sensitivity and resistance, and to develop rational immune-based combination strategies that prevent or delay the emergence of drug resistant clones.

定义肿瘤内形态学，免疫和突变异质性对尿路上皮的影响 癌 膀胱癌是全球第九大癌症，也是男性第四大癌症。尽管 密集的多模式疗法，大约50％的肌肉侵入性疾病患者遥远 从历史上看，这种患者对长期生存的希望很小。免疫的发展 检查点抑制剂是三十年来膀胱癌中最重要的治疗疗法， 这些代理的开发为许多先前无法治愈的转移性患者提供了新的希望 疾病。抗PD1/PD-L1抗体可以诱导转移性膀胱患者的耐用完全反应 现在，具有几种免疫检查点抑制剂的癌症已被FDA批准为此指示。但是， 大多数转移性尿路上皮癌患者不会受益于免疫检查点封锁和一些 最初反应的患者会产生获得的抵抗。先天和获得的生物学基础 尿路上皮癌中免疫检查点阻滞的耐药性仍然很差。尿路上皮癌显示 在单个肿瘤中经常共存的各种变异形态。我们已经证明了这一点 形态异质性通常与肿瘤内突变异质性有关。当前的建议 是基于初步数据，表明膀胱癌的形态异质性与 基因组和免疫异质性，可以预测对阿托唑珠单抗的反应较差（抗PD-L1 抑制剂）。提出了三个目标。在AIM 1中，我们将执行整合的组织学，基因类和免疫 对成对，宏观删除，形态上不同的区域与形态异质性肿瘤的分析 从接受免疫检查点封锁治疗的患者来定义肿瘤内的患病率和程度 遗传和免疫异质性。在AIM 2中，这些组织分析研究将与详细的临床集成 患者响应数据以定义先前存在的组织学，基因组和免疫异质性的作用 确定对系统性免疫疗法的反应。最后，在AIM 3中，我们将研究收集的肿瘤 接受免疫检查点抑制剂治疗的患者的疾病进展，以确定是否存在药物 抗性克隆存在于形态上异质的原发性肿瘤中，并且这些较少 免疫原性癌细胞是患者耐药性和疾病进展的基础 形态上异质性肿瘤。长期翻译目标将是使用生物学见解 获得了改善免疫疗法敏感性和耐药性的生物标志物，并发展有理 基于免疫的组合策略，可防止或延迟耐药克隆的出现。