Pathway-guided treatment of immune checkpoint inhibitor therapy-induced colon toxicity

免疫检查点抑制剂治疗引起的结肠毒性的路径引导治疗

• 批准号: 10752985
• 负责人: Jeffrey A Sosman
• 金额: $ 66.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752985
• 关键词: Address; Adopted; Adrenal Cortex Hormones; Adverse effects; Animal Model; Antibodies; Antibody Therapy; Archives; Autoimmune; Biochemical; Biochemical Markers; Biopsy; CD8-Positive T-Lymphocytes; Cancer Patient; Circulation; Clinical; Clinical Trials; Code; Colitis; Colon; Colonic inflammation; Development; Enterocolitis; Failure; Genetic Engineering; Grant; Guidelines; Human; IL18 gene; Immune; Immune checkpoint inhibitor; Inflammatory Bowel Diseases; Institution; Integrins; Intestines; Ligands; Manuscripts; Mediating; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Oncogenic; Outcome; PD-1/PD-L1; Pathway interactions; Patients; Pilot Projects; Production; Prostatic Neoplasms; Refractory; Reporting; Sampling; Science; Serum; Source; Steroids; TNF gene; Toxic effect; Work; anti-CTLA-4 therapy; anti-CTLA4; anti-PD-1; autoimmune inflammatory bowel disease; cancer immunotherapy; cancer therapy; checkpoint therapy; cohort; cytotoxicity; effective therapy; immune activation; immunoregulation; improved; inflammatory milieu; integrin alpha4beta7; molecular pathology; molecular subtypes; mouse model; novel; patient subsets; pre-clinical; prevent; standard care; tumor

Abstract Development of immune-related adverse effects (irAEs) is one of the significant challenges of current approved cancer therapy with immune checkpoint inhibitors (ICIs) of targeting anti-CTLA4 and/or anti-PD1/PDL1. Immune- mediated enterocolitis or inflammatory bowel disease is one of the most frequent and problematic irAE associated with ICI therapy (simplistically termed “ICI-colitis” in the grant). The development of severe ICI- associated enterocolitis is the most frequent cause of ICI therapy cessation and significant morbidity, which inevitably impedes the clinical benefits of ICI therapy. The underlying mechanism of ICI-colitis remains poorly understood. Due to the lack of mechanistic understanding, current treatment of ICI-colitis was empirically adopted from the approaches for the idiopathic inflammatory bowel diseases (IBD), using corticosteroids as the 1st line treatment and targeted anti-TNFα or anti-α4β7 integrin as the 2nd line treatment for corticosteroid failures. For patients with severe ICI-colitis, this approach frequently resulted in a significant delay in resuming ICI therapy or forced permanent cessation of ICI therapy, owing to the complications of corticosteroid use itself. Clearly, it is imperative to understand the molecular and cellular pathways of ICI-colitis to guide a more scientific and effective management and to achieve better clinical outcomes. In our preliminary studies with colon biopsies from a small cohort (n=18) of ICI-colitis patients, we discovered that ICI-colitis presented two subtypes by molecular pathology and the associated responsiveness to corticosteroid treatment. One subtype has the signature of CD8 T cell cytotoxicity in the colon and responsiveness to corticosteroids, whereas the other subtype has the molecular signature of the idiopathic IBD and is refractory to corticosteroids but responsive to the 2nd line treatment. The former type was associated with elevated tumor-secreted circulating soluble NKG2D ligand sMIC in the colon and elevated serum IL-18. Notably, we have established unique animal models to recapitulate the sMIC- associated ICI-colitis subtype. With our novel clinical findings and unique animal models, the objectives of this proposed study are: 1) to establish clinically achievable biochemical parameters that can be used to guide a more effective treatment of ICI-colitis through leveraging a larger cohort of archived clinically-annotated ICI-colitis patient samples; 2) to understand the cellular and molecular mechanisms underlying the subset of ICI-colitis associated with elevated circulating sMIC and IL-18; and 3) to explore more beneficial treatments for sMIC- associated ICI-colitis preclinically. Through the perpetual dialogue between human samples and mouse models, we anticipate that our study will provide the rationales for multi-institutional large cohort clinical trials to validate the parameters for guiding a more effective ICI-colitis management and for a more beneficial therapy to treat ICI- colitis in a subset of patients.

抽象的 免疫相关不良反应（irAE）的发生是当前批准的药物面临的重大挑战之一 使用针对 CTLA4 和/或 PD1/PDL1 的免疫检查点抑制剂 (ICIs) 进行癌症治疗。免疫- 介导的小肠结肠炎或炎症性肠病是最常见和最有问题的 irAE 之一 与 ICI 治疗相关（在拨款中简单地称为“ICI-结肠炎”）。严重 ICI 的发展 相关小肠结肠炎是 ICI 治疗停止和显着发病率的最常见原因， 不可避免地会阻碍 ICI 治疗的临床益处。 ICI-结肠炎的潜在机制仍不清楚 明白了。由于缺乏机制了解，目前 ICI 结肠炎的治疗主要是凭经验进行的。 采用了治疗特发性炎症性肠病（IBD）的方法，使用皮质类固醇作为治疗方法 一线治疗和靶向抗 TNFα 或抗 α4β7 整合素作为皮质类固醇失败的二线治疗。 对于患有严重 ICI 结肠炎的患者，这种方法经常导致恢复 ICI 治疗的显着延迟 或由于皮质类固醇使用本身的并发症而被迫永久停止 ICI 治疗。显然，它是 了解ICI-结肠炎的分子和细胞通路势在必行，以指导更科学有效的治疗 管理并取得更好的临床效果。在我们对小样本结肠活检的初步研究中 在 ICI 结肠炎患者队列（n = 18）中，我们发现 ICI 结肠炎通过分子病理学呈现两种亚型 以及对皮质类固醇治疗的相关反应。一种亚型具有 CD8 T 细胞的特征 结肠中的细胞毒性和对皮质类固醇的反应性，而其他亚型具有分子 特发性 IBD 的特征，对皮质类固醇无效，但对二线治疗有反应。这 前一种类型与结肠中肿瘤分泌的循环可溶性 NKG2D 配体 sMIC 升高相关 以及血清 IL-18 升高。值得注意的是，我们建立了独特的动物模型来概括 sMIC- 相关 ICI-结肠炎亚型。凭借我们新颖的临床发现和独特的动物模型，该研究的目标 拟议的研究是：1）建立临床上可实现的生化参数，可用于指导 通过利用更大的临床注释 ICI 结肠炎存档队列，更有效地治疗 ICI 结肠炎 患者样本； 2) 了解 ICI-结肠炎亚型背后的细胞和分子机制 与循环 sMIC 和 IL-18 升高相关； 3) 探索更有益的 sMIC 治疗方法- 相关的 ICI-结肠炎临床前。通过人类样本和小鼠模型之间的永恒对话， 我们预计我们的研究将为多机构大型队列临床试验提供理论依据以验证 指导更有效的 ICI 结肠炎管理和更有益的治疗 ICI 的参数 一部分患者患有结肠炎。