Mechanisms of liver metastasis and associated resistance to immunotherapy

肝转移的机制和相关的免疫治疗耐药性

基本信息

批准号：
10818003
负责人：
Benjamin Izar
金额：
$ 14.49万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-09 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10818003
关键词：
Academic Medical Centers Advanced Malignant Neoplasm Aftercare Applications Grants Back Biological Biopsy Cells Clear cell renal cell carcinoma Clinical Clinical Trials Clonality Combined Modality Therapy Data Set Disease Dose Drug resistance Endothelial Growth Factors Receptor Evaluation Extrahepatic Freezing Fresh Tissue Funding Genomic approach Genomics Goals Grant Image Immune checkpoint inhibitor Immunofluorescence Immunologic Immunotherapy Infiltration Institution Interleukin-2 Laboratories Malignant Neoplasms Malignant neoplasm of lung Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Methods Modeling Molecular Myeloid-derived suppressor cells Nivolumab Outcome Patient Care Patient Selection Patients Pharmaceutical Preparations Preclinical Testing RNA Resistance Resolution Role Site Specimen Structure T cell clonality T cell receptor repertoire sequencing T-Cell Receptor TNFSF15 gene Technology Testing Therapeutic Tissues Toxic effect Vascular Endothelial Growth Factors Work cancer cell cancer immunotherapy checkpoint therapy clinically relevant cohort combinatorial complex data computer framework cytotoxic CD8 T cells experience genome sequencing immune cell infiltrate improved inhibitor inhibitor therapy multimodal data multimodality novel patient stratification predicting response programs resistance mechanism response spatiotemporal transcriptome sequencing tumor tumor microenvironment whole genome

项目摘要

PROJECT SUMMARY Cancer immunotherapies have revolutionized the therapy of many cancers, including metastatic melanoma and clear cell renal cell carcinoma (ccRCC). Dating back 30 years, the first cancer immunotherapy, high-dose interleukin-2, was successfully tested in melanoma and ccRCC and provided a first proof-of-concept of a transformative therapeutic potential.1-3 In the last decade, melanoma and ccRCC have represented archetypical diseases, in which a portion of patients experience durable responses to novel immunotherapies, such as immune checkpoint inhibitors (ICI), and these observations frequently extrapolated to other cancers as well (e.g., lung cancer). 4-8 However, most patients do not response to ICI and the underlying mechanisms are unclear. In our initially funded grant (R37CA258829), we explore the role of liver metastasis and their role in conferring resistance to ICI, both locally and in concurrent metastatic sites (e.g., lung metastases). We leverage cutting-edge models and technologies, including single-cell genomics, to dissect this clinically relevant predictor for ICI resistance, and explore opportunities for pre- clinical testing of combination therapies that may help overcoming resistance to ICI. In the current proposal, we will expand on these initial studies and study molecular predictors of response and resistance in patients with metastatic ccRCC who are treated with a combination of ICI and inhibitors of vascular endothelial growth factor receptors (VEGFR). For this purpose, we have collected paired snap-frozen tissue specimens from patients before therapy and after a course of ICI and VEGFR inhibitor therapy. In preliminary studies, we applied cutting-edge technologies developed in our laboratory to enable multi-modal single-cell genomics from frozen tissues achieving excellent technical quality. Furthermore, we established panels for multiplexed immunofluorescence (mIF) on matching tissues. In Aim 1, we will perform mIF on determining spatio-temporal effects of ICI + VEGFR inhibitor therapy, and correlate changes in immune infiltrates with clinical outcomes. In Aim 2, we will perform multi-modal single-cell genomics, including RNA-sequencing and T cell receptor sequencing (TCR) to determine both cancer cell intrinsic and extrinsic molecular and clonal correlates of response and resistance at single-cell resolution. Together with the proposed work in the initial grant application, this supplement will further enhance our understanding of molecular and cellular correlates of response and resistance to immunotherapies.

项目概要癌症免疫疗法彻底改变了许多癌症的治疗方法，包括转移性癌症黑色素瘤和透明细胞肾细胞癌（ccRCC）。距今 30 年前，第一种癌症免疫疗法，即高剂量白介素-2，已在黑色素瘤和 ccRCC 中成功进行了测试，提供了变革性治疗潜力的第一个概念验证。1-3 在过去十年中，黑色素瘤和 ccRCC 是典型疾病，其中一部分患者对新型免疫疗法（例如免疫检查点抑制剂）产生持久反应（ICI），这些观察结果也经常推断到其他癌症（例如肺癌）。 4-8 然而，大多数患者对 ICI 没有反应，其潜在机制尚不清楚。在我们最初资助的赠款（R37CA258829）中，我们探索了肝转移的作用及其作用赋予对 ICI 的抵抗力，无论是局部还是同时的转移部位（例如，肺）转移）。我们利用尖端模型和技术，包括单细胞基因组学、剖析这个 ICI 耐药的临床相关预测因素，并探索预防的机会联合疗法的临床测试可能有助于克服 ICI 耐药性。在当前建议，我们将扩展这些初步研究并研究反应的分子预测因子和接受 ICI 和联合治疗的转移性 ccRCC 患者的耐药性血管内皮生长因子受体（VEGFR）抑制剂。为此，我们有在治疗前和一个疗程后从患者身上收集了配对的速冻组织标本 ICI 和 VEGFR 抑制剂治疗。在前期研究中，我们应用了尖端技术我们实验室开发的用于从冷冻组织中进行多模式单细胞基因组学实现卓越的技术品质。此外，我们还建立了多路复用面板匹配组织上的免疫荧光（mIF）。在目标 1 中，我们将执行 mIF 来确定 ICI + VEGFR 抑制剂治疗的时空效应以及免疫变化的相关性渗透到临床结果中。在目标 2 中，我们将进行多模式单细胞基因组学，包括 RNA 测序和 T 细胞受体测序 (TCR)，以确定癌细胞单细胞反应和耐药性的内在和外在分子和克隆相关性解决。连同最初拨款申请中拟议的工作，该补充文件将进一步增强我们对反应的分子和细胞相关性的理解对免疫疗法的抵抗。