Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors

检查点抑制剂引起的免疫相关毒性的基于机制的治疗策略

• 批准号: 10753628
• 负责人: Roza Insafetdinovna Nurieva
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753628
• 关键词: Address; Advanced Malignant Neoplasm; Arthritis; Autoimmunity; Biological Markers; Bronchoalveolar Lavage; CTLA4 gene; Cancer Patient; Cells; Clinical; Clinical Research; Colitis; Colon; Development; Disease; Goals; Hospitalization; Human; Immune; Immune checkpoint inhibitor; Immunity; Immunology; Immunotherapy; Individuality; Interleukin-6; Knowledge; Life; Lung; Maintenance; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathogenicity; Patients; Phenotype; Play; Pulmonary Inflammation; Reagent; Research; Research Personnel; Role; Safety; Sampling; Severities; Severity of illness; Steroids; Synovial Fluid; Synovial Membrane; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tumor Immunity; Work; autoimmune toxicity; cancer immunotherapy; cancer therapy; checkpoint therapy; cytokine; efficacy evaluation; experience; fecal transplantation; immune-related adverse events; improved; in vivo; inhibitor; melanoma; microbiome; mouse model; novel; pre-clinical; predictive marker; preservation; programmed cell death protein 1; response; success; targeted treatment; therapeutic biomarker; therapeutic evaluation; therapeutic target; transcriptomics; translational study; treatment strategy; tumor; tumor immunology

PROJECT SUMMARY/ABSTRACT Although immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, they are associated with life- or organ-threatening complications, termed immune-related adverse events (irAEs). Steroids, the first-line of treatment for irAEs, significantly abrogate the anti-tumor efficacy of ICIs; however, our knowledge of the mechanisms and signs that underpin the onset and progression of irAEs is very limited. Furthermore, commonality and individuality of altered immunity between irAEs have never been characterized. Our clinical and translational studies have revealed significant impact of combined ICI therapy (cytotoxic T lymphocyte- associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors) on the severity of arthritis-irAE, -colitis-irAE, and -pneumonitis-irAE compared to PD-1 inhibitor monotherapy. Notably, T helper (Th)17 cell signatures were significantly enhanced in arthritis-irAE synovial fluid, colitis-irAE colon, and pneumonitis-irAE bronchoalveolar lavage. In parallel, our lab has developed arthritis-irAE, colitis-irAE and pneumonitis-irAE murine models recapitulating patients’ clinical settings. Importantly, like in humans, Th17 cell signatures were enriched in the inflamed tissue of mice with ICI-induced arthritis (synovium), colitis (colon), and pneumonitis (lung) after combined ICI-therapy and correlated with irAE disease severity. Interestingly, arthritis-prone mice developed arthritis after receiving fecal microbial transplant (FMT) from combined ICI arthritis donor mice, notably with enhanced Th17 cell signatures. We also observed that blockade of Th17- related cytokines, interleukin (IL)-6 and tumor necrosis factor alpha (TNFα), may pinpoint irAE immunity while preserving/enhancing the anti-tumor efficacy of ICI therapy in humans and mice. Further understanding of mechanisms underlying irAEs may lead to identification of common and valid biomarkers predicting development and/or reflecting severity of irAEs as well as to new steps in their treatment. Therefore, we propose to uncover shared and distinct cellular/molecular mechanism(s) underpinning irAEs (arthritis- irAE, colitis-irAE, and pneumonitis-irAE) development as well as establish efficient therapeutic strategies. Here, in Aim 1, we will identify the cellular and molecular mechanisms and therapeutic targets by utilizing our novel preclinical murine models of irAEs including arthritis, colitis, and pneumonitis. In addition, cellular, phenotypic, and transcriptomic analysis of biospecimens from cancer patients with arthritis-irAE, colitis-irAE or pneumonitis-irAE will help to uncover common or unique immunopathogenesis mechanisms between different irAEs. In Aim 2, we will develop optimal strategies for treatment of irAEs while preserving anti-tumor immunity by utilizing melanoma tumor model in mice with irAEs. The implications from this work will be significant and will help to: 1) discover mechanisms universally or distinctively present in irAEs; 2) identify mechanistic biomarkers reflecting irAE disease activity; and most importantly, 3) develop a mechanism-rooted therapeutic strategy for irAEs without sacrificing anti-tumor immunity.

项目摘要/摘要 尽管免疫切除点抑制剂（ICI）正在彻底改变癌症治疗，但它们与 生命或威胁器官的并发症，称为免疫相关的广告事件（IRAE）。类固醇，一线 伊拉斯的治疗，显着消除了ICIS的抗肿瘤效率；但是，我们对 支撑伊拉斯的发作和进展的机制和迹象非常有限。此外， 伊拉斯之间的免疫抑制改变的通用性和个性从未被表征。我们的临床 翻译的研究表明，ICI疗法联合治疗的重大影响（细胞毒性T淋巴细胞 - 相关的抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）抑制剂）在严重程度上 与PD-1抑制剂单一疗法相比，关节炎IRAE，-Colisis-IRAE和-Pneumonis-IRAE。值得注意的是，T助手 （TH）关节炎滑液，结肠炎结肠和 肺炎 - IRAE支气管肺泡灌洗。同时，我们的实验室发展了关节炎，结肠炎和结肠炎和 肺炎IRAE鼠模型概括了患者的临床环境。重要的是，像人类一样，Th17细胞 通过ICI诱导的关节炎（滑膜），结肠炎（结肠），富含特征在小鼠的发炎组织中富含特征。 ICI疗法结合后，与IRAE疾病严重程度相关后，肺炎（肺）和肺炎。有趣的是， 易受关节炎的小鼠从联合ICI接收粪便微生物移植（FMT）后出现关节炎 关节炎供体小鼠，特别是具有增强的Th17细胞特征。我们还观察到Th17-的封锁 相关的细胞因子，白介素（IL）-6和肿瘤坏死因子α（TNFα），可以确定IRAE免疫力 保留/提高人类和小鼠ICI治疗的抗肿瘤效率。进一步理解 伊拉斯的机制可能导致鉴定常见和有效的生物标志物预测 开发和/或反映了伊拉斯的严重程度以及对其治疗的新步骤。因此，我们 提议揭示共同且独特的细胞/分子机制（S）的基础（关节炎） IRAE，结肠炎IRAE和肺炎IRAE）发育以及确定的有效治疗 策略。在此，在AIM 1中，我们将通过 使用我们新颖的伊拉斯临床前鼠模型，包括关节炎，结肠炎和肺炎。此外， 来自关节炎的癌症患者的生物测量的细胞，表型和转录组分析， 结肠炎或肺炎 - IRAE将有助于发现常见或独特的免疫病变机制 在不同的伊拉斯之间。在AIM 2中，我们将制定最佳策略来保存伊拉斯 通过在伊拉斯小鼠中使用黑色素瘤模型，抗肿瘤免疫。这项工作的含义将 要重要，并将有助于：1）在伊拉斯中普遍或明显地发现机制； 2）识别 反映IRAE疾病活动的机械生物标志物；最重要的是，3）开发一个根源的机制 伊拉斯的治疗策略而无需牺牲抗肿瘤免疫。