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

摘要 免疫相关不良反应（irAE）的发生是目前批准的免疫治疗的重大挑战之一。 使用靶向抗CTLA 4和/或抗PD 1/PDL 1的免疫检查点抑制剂（ICI）的癌症治疗。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（在资助中简单地称为“ICI-结肠炎”）。严重ICI的发展- 相关性小肠结肠炎是ICI治疗停止和显著发病的最常见原因， 不可避免地阻碍了ICI疗法的临床益处。ICI结肠炎的潜在机制仍然很差 明白由于缺乏对机制的理解，目前ICI结肠炎的治疗是经验性的。 采用了特发性炎症性肠病（IBD）的方法，使用皮质类固醇作为 一线治疗和靶向抗TNF α或抗α4β7整联蛋白作为皮质类固醇治疗失败的二线治疗。 对于重度ICI结肠炎患者，这种方法经常导致ICI治疗恢复的显著延迟 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。很明显， 必须了解ICI-结肠炎的分子和细胞途径，以指导更科学有效的治疗。 管理和实现更好的临床结果。在我们的初步研究中， 通过对18例ICI-结肠炎患者的队列研究，我们发现ICI-结肠炎通过分子病理学表现出两种亚型 以及对皮质类固醇治疗的相关反应性。一种亚型具有CD 8 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，而另一种亚型具有分子 特发性IBD的特征，对皮质类固醇难治，但对二线治疗有反应。的 前者与结肠中肿瘤分泌的循环可溶性NKG 2D配体sMIC升高相关 血清IL-18水平升高值得注意的是，我们已经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， 建议的研究是：1）建立临床上可实现的生化参数，可用于指导 通过利用更大的存档临床注释ICI结肠炎队列，更有效地治疗ICI结肠炎 患者样本; 2）了解ICI-结肠炎亚组的细胞和分子机制 与升高的循环sMIC和IL-18相关;和3）探索更有益的sMIC治疗， 临床前相关ICI结肠炎。通过人类样本和小鼠模型之间的永久对话， 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基础， 指导更有效的ICI结肠炎管理和更有益的ICI治疗的参数， 结肠炎患者的一个子集。

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.