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.

项目总结/摘要 尽管免疫检查点抑制剂（ICI）正在彻底改变癌症治疗，但它们与 危及生命或器官的并发症，称为免疫相关不良事件（irAE）。类固醇，第一线 治疗irAE，显著消除了ICI的抗肿瘤疗效;然而，我们对 支持irAE发生和进展的机制和体征非常有限。此外，委员会认为， irAE之间免疫改变的共性和个性从未被表征。我们的临床 和翻译研究已经揭示了联合ICI疗法（细胞毒性T淋巴细胞- 相关抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）抑制剂）对 与PD-1抑制剂单一疗法相比，关节炎-irAE、结肠炎-irAE和肺炎-irAE。值得注意的是，T辅助细胞 （Th）17细胞标记在关节炎-irAE滑液、结肠炎-irAE结肠和 肺炎-irAE支气管肺泡灌洗。同时，我们的实验室已经开发了关节炎-irAE，结肠炎-irAE和 肺炎-irAE鼠模型重现患者的临床环境。重要的是，像人类一样，Th 17细胞 在患有ICI诱导的关节炎（滑膜），结肠炎（结肠）， 和肺炎（肺）后，联合ICI治疗，并与irAE疾病的严重程度。有趣的是， 关节炎易感小鼠在接受来自联合ICI的粪便微生物移植（FMT）后发生关节炎 关节炎供体小鼠，特别是具有增强的Th 17细胞特征。我们还观察到阻断Th 17- 相关的细胞因子，白细胞介素（IL）-6和肿瘤坏死因子α（TNFα），可以精确定位irAE免疫， 保持/增强ICI疗法在人和小鼠中的抗肿瘤功效。进一步理解 irAE的潜在机制可能导致识别预测irAE的常见和有效的生物标志物。 发展和/或反映irAE的严重程度以及其治疗的新步骤。所以我们 建议揭示共同的和不同的细胞/分子机制，支持irAE（关节炎- irAE、结肠炎-irAE和肺炎-irAE）发展以及建立有效的治疗 战略布局在这里，在目标1中，我们将通过以下方法确定细胞和分子机制以及治疗靶点： 利用我们的新型irAE临床前小鼠模型，包括关节炎、结肠炎和肺炎。此外，本发明还提供了一种方法， 关节炎-irAE癌症患者生物样本的细胞、表型和转录组学分析， 结肠炎-irAE或肺炎-irAE将有助于揭示共同或独特的免疫发病机制 不同的irae。在目标2中，我们将制定治疗irAE的最佳策略，同时保留 利用irAE小鼠黑色素瘤模型的抗肿瘤免疫。这项工作的影响将 具有重要意义，将有助于：1）发现irAE中普遍存在或独特存在的机制; 2）识别 反映irAE疾病活动的机制生物标志物;最重要的是，3）开发一种机制， irAE的治疗策略，而不牺牲抗肿瘤免疫力。