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

• 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
• 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' 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

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.

项目摘要 ipilimumab（抗CTLA-4）和nivolumab（抗PD-1）的第一个联合免疫疗法被批准用于 2015年，与纳武单抗单独治疗相比，黑色素瘤患者的无进展生存期更长（11.5 vs. 6.9 月），53%的患者在4年时仍然存活，其中71%的患者仍然没有接受治疗。然而，安全是 更广泛地实施这一成功组合的最大障碍是， 严重免疫相关不良事件（irAE）。特别是与免疫相关的 结肠炎（irColitis）是最常见的疾病，10-15%的患者在接受抗结肠炎药物治疗后发生结肠炎。 单独或组合的CTLA-4。这种irColitis是危及生命的，需要立即治疗高- 剂量类固醇或生物制剂，如抗TNF，以及ipilimumab或免疫治疗中止。这些 安全性问题阻碍了CTLA-4靶向药物的开发， 由于联合治疗中推荐剂量较低和疗程有限，因此疗效不佳。有 因此，迫切需要全面研究irColitis的性质，并找到潜在的危险因素， 可以识别和缓解，以提高联合治疗的安全性和有效性。 我们组建了一个独特的团队，由炎症性肠病（IBD）科学家和临床医生、肿瘤 免疫学家、微生物组专家和专门从事黑色素瘤免疫治疗的医学肿瘤学家， 分析结直肠组织病变、肠道微生物组和外周血生物标志物， 有助于irColitis的发展。通过比较我们已经从研究生物标本中了解到的 IBD患者，即，它们在单细胞水平上的遗传亚群，肠道微生物组和预测免疫 签名，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 irColitis的景观和利用这些知识更好的治疗选择。 我们将通过在使用单克隆抗体治疗期间对黑色素瘤患者的肠道活检进行表征来解决irColitis。 细胞RNA测序和多重免疫组织化学作图，我们将把免疫亚群和 发现的标志物与IBD病变中发现的标志物。我们还将测量外周血血清学标志物 （通过ELISA测定抗微生物和抗GM-CSF自身抗体，通过Olink测定可溶性细胞因子和蛋白质分析物） 邻近延伸试验），我们最近发现是IBD发展前可检测到的风险因素， 分析它们预测irColitis的能力。从治疗前和治疗过程中收集的粪便中，我们 将通过16 S和宏基因组测序分析黑色素瘤患者的肠道微生物组， irColitis将其与IBD中已知的大肠杆菌结构进行比较，并对IBD中的细菌群落进行功能评估 知生模式最后，我们将整合我们的研究结果，建立一个机制模型的irColitis比较 IBD，提出新的分层癌症免疫治疗患者的危险因素，并提供未来 治疗机会，如可操作的组织基因组和蛋白质靶点或粪便移植。