Characterizing and predicting colitis in immune checkpoint blockade-treated cancer patients

免疫检查点阻断治疗癌症患者结肠炎的特征和预测

基本信息

批准号：
10176481
负责人：
Jean-Frederic Colombel
金额：
$ 57.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10176481
关键词：
16S ribosomal RNA sequencing Address Antibodies Autoantibodies Biological Biological Assay Biological Markers Biopsy Blood CTLA4 blockade CTLA4 gene Cancer Patient Cells Clinic Clinical Clinical Trials Design Colitis Colorectal Combination immunotherapy Combined Modality Therapy Crohn&apos s disease Data Development Disease remission Dose Enzyme-Linked Immunosorbent Assay Feces Flowers Future Genetic Genomics Gnotobiotic Goals Granulocyte-Macrophage Colony-Stimulating Factor Immune Immune Targeting Immunohistochemistry Immunologist Immunotherapy Inflammatory Bowel Diseases Intestines Knowledge Lamina Propria Lesion Life Malignant Neoplasms Measures Medical Oncologist Modeling Monoclonal Antibodies Nature Nivolumab Patient risk Patients Pharmaceutical Preparations Predictive Value Progression-Free Survivals Proteins Proteomics Risk Factors Safety Scientist Serology Serum Serum Markers Specialist Specimen Steroids Stratification Structure Symptoms TNF gene Testing Therapeutic Tissues Treatment Side Effects Ulcerative Colitis anti-CTLA4 anti-PD-1 antimicrobial bacterial community base cancer immunotherapy clinical development cytokine density fecal transplantation frontier gut microbiome gut microbiota immune checkpoint immune checkpoint blockade immune-related adverse events improved ipilimumab melanoma metagenomic sequencing microbial microbiome microbiome analysis microbiome composition microbiome signature novel patient subsets peripheral blood predictive marker prospective response serological marker single cell analysis single-cell RNA sequencing targeted agent transcriptomics treatment response tumor tumor-immune system interactions

项目摘要

PROJECT SUMMARY The first combination immunotherapy of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) approved for melanoma in 2015 has achieved longer progression-free survival compared to nivolumab alone (11.5 vs. 6.9 months), with 53% of patients still alive at 4 years, of whom 71% remain treatment free. Yet, safety is the biggest barrier to broader implementation of this successful combination, due to much greater occurrence of serious immune-related adverse events (irAEs) compared to nivolumab alone. In particular, immune-related colitis (irColitis) is the most common occurrence, with 10-15% of patients developing it upon receiving anti- CTLA-4 alone or in combinations. Such irColitis is life-threatening and requires immediate treatment with high- dose steroids or biologics such as anti-TNF, as well as ipilimumab or immunotherapy discontinuation. These safety concerns have hampered the development of CTLA-4 targeting agents and may have reduced their efficacy due to lower recommended dosing in combination therapy and limited treatment course. There is therefore an urgent need to comprehensively study the nature of irColitis and find whether potential risk factors could be identified and mitigated for greater safety and efficacy of combination treatments. We have assembled a unique team of inflammatory bowel disease (IBD) scientists and clinicians, tumor immunologists, microbiome specialists, and medical oncologists specializing in immunotherapy of melanoma to analyze colorectal tissue lesions, the gut microbiome, and peripheral blood biomarkers that could predict or contribute to development of irColitis. By comparing what we already learned from studying biospecimens of IBD patients, i.e., their genetic subsets at the single cell level, gut microbiome, and predictive immune signatures, we aim to characterize the transcriptomic, immunopathologic, serologic, and gut microbiome landscape of irColitis and leverage this knowledge for better therapeutic options. We will address irColitis by characterizing gut biopsies of melanoma patients during treatment using single- cell RNA sequencing and multiplex immunohistochemistry mapping, and we will relate immune subsets and markers discovered to those found in IBD lesions. We will also measure peripheral blood serologic markers (anti-microbial and anti-GM-CSF autoantibodies by ELISA, soluble cytokine and protein analytes with Olink proximity extension assay) that we recently found to be risk factors detectable prior to development of IBD, and analyze them for their capacity to predict irColitis. From stool collected before and throughout treatment, we will analyze by 16S and metagenomic sequencing the gut microbiome of melanoma patients with or without irColitis to compare it to known colitogenic structure in IBD, and functionally assess bacterial communities in gnotobiotic models. Finally, we will integrate our findings to establish a mechanistic model of irColitis compared to IBD, to propose novel stratifications of cancer immunotherapy patients by risk factors, and to offer future therapeutic opportunities, such as actionable tissue genomic and protein targets or fecal transplants.

项目概要首个 ipilimumab（抗 CTLA-4）和 nivolumab（抗 PD-1）联合免疫疗法获批与单用纳武单抗相比，2015 年黑色素瘤实现了更长的无进展生存期（11.5 vs. 6.9）月），53% 的患者在 4 岁时仍然存活，其中 71% 的患者无需接受治疗。然而，安全才是重中之重更广泛地实施这一成功组合的最大障碍是，由于与单用纳武单抗相比，出现严重的免疫相关不良事件（irAE）。特别是与免疫相关的结肠炎 (irColitis) 是最常见的疾病，10-15% 的患者在接受抗药治疗后出现该病 CTLA-4单独或组合。这种结肠炎会危及生命，需要立即进行高强度治疗。服用类固醇或生物制剂（例如抗 TNF），以及停止伊匹单抗或免疫治疗。这些安全问题阻碍了 CTLA-4 靶向药物的开发，并可能降低了其疗效由于联合治疗中推荐剂量较低且疗程有限，因此疗效不佳。有因此迫切需要全面研究结肠炎的性质并寻找是否存在潜在的危险因素可以识别和缓解，以提高联合治疗的安全性和有效性。我们组建了一支由炎症性肠病（IBD）科学家和临床医生组成的独特团队，肿瘤专门从事黑色素瘤免疫治疗的免疫学家、微生物组专家和医学肿瘤学家分析结直肠组织病变、肠道微生物组和外周血生物标志物，可以预测或有助于结肠炎的发展。通过比较我们从生物样本研究中学到的知识 IBD 患者，即其单细胞水平的遗传子集、肠道微生物组和预测性免疫特征，我们的目标是表征转录组学、免疫病理学、血清学和肠道微生物组了解结肠炎的情况，并利用这些知识来获得更好的治疗选择。我们将通过对黑色素瘤患者在治疗期间的肠道活检进行表征来解决结肠炎问题，使用单细胞 RNA 测序和多重免疫组织化学作图，我们将把免疫亚群与在 IBD 病变中发现的标记物。我们还将测量外周血血清学标志物（通过 ELISA 检测抗微生物和抗 GM-CSF 自身抗体，通过 Olink 检测可溶性细胞因子和蛋白质分析物我们最近发现在 IBD 发生之前可检测到危险因素，以及分析它们预测结肠炎的能力。从治疗前和整个治疗过程中收集的粪便中，我们将通过 16S 和宏基因组测序分析患有或不患有黑色素瘤患者的肠道微生物组 irColitis 将其与 IBD 中已知的致结肠炎结构进行比较，并功能性评估 IBD 中的细菌群落知生模型。最后，我们将整合我们的研究结果来建立一个比较的结肠炎机制模型向 IBD 提出按危险因素对癌症免疫治疗患者进行新的分层，并为未来提供建议治疗机会，例如可操作的组织基因组和蛋白质靶标或粪便移植。