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

基本信息

批准号：
10559665
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
项目类别：
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/10559665
关键词：
Address Antibodies Area Biological Biological Markers CD8B1 gene Cancer Patient Cd68 Clinical Clinical Trials Clonality Collection Combined Modality Therapy Data Development Disease Disease Progression Disease Resistance Distant Metastasis Drug resistance Evaluation Exhibits FDA approved FOXP3 gene 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-cell receptor repertoire Therapeutic Time Tissues Transitional Cell Carcinoma Treatment Failure Treatment outcome Tumor-infiltrating immune cells Urothelium Variant anti-PD-1 anti-PD-L1 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 response standard care transcriptome transcriptome sequencing treatment response tumor tumor heterogeneity tumor progression

项目摘要

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、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常见癌症，也是男性第四大常见癌症。尽管强化多学科治疗，大约 50% 的肌肉侵袭性疾病患者会出现远处转移转移以及历史上此类患者长期生存的希望渺茫。免疫的发展检查点抑制剂是三十年来膀胱癌最重要的治疗进展这些药物的开发为许多以前无法治愈的转移性患者带来了新的希望疾病。抗 PD1/PD-L1 抗体可诱导转移性膀胱患者持久完全缓解具有多种免疫检查点抑制剂的癌症现已获得 FDA 批准用于该适应症。然而，大多数转移性尿路上皮癌患者无法从免疫检查点阻断中受益，有些患者则无法从免疫检查点阻断中获益。最初有反应的患者后来出现获得性耐药。先天和后天的生物学基础尿路上皮癌对免疫检查点阻断的抵抗力仍然不明确。尿路上皮癌显示各种形态变异通常共存于单个肿瘤内。我们已经证明这形态异质性通常与肿瘤内突变异质性相关。目前的提案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，并且预测对 atezolizumab（一种抗 PD-L1 药物）的反应较差抑制剂）。提出了三个目标。在目标 1 中，我们将进行综合组织学、基因组学和免疫学研究对来自形态异质肿瘤的配对、宏观解剖、形态不同的区域进行分析来自接受免疫检查点阻断治疗的患者，以确定肿瘤内肿瘤的患病率和范围遗传和免疫异质性。在目标 2 中，这些组织分析研究将与详细的临床研究相结合和患者反应数据来定义预先存在的组织学、基因组和免疫异质性在疾病中的作用确定对全身免疫治疗的反应。最后，在目标 3 中，我们将研究在使用免疫检查点抑制剂治疗的患者的疾病进展以确定是否预先存在药物耐药克隆存在于形态异质的原发肿瘤中，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异质性肿瘤。长期转化目标将是利用生物学见解开发改进的免疫治疗敏感性和耐药性生物标志物，并开发合理的基于免疫的组合策略，防止或延迟耐药克隆的出现。