Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities

肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用

基本信息

批准号：
10263391
负责人：
Brent Allen Hanks
金额：
$ 39.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263391
关键词：
Address Adjuvant Antibody Therapy Arthritis CD8-Positive T-Lymphocytes Cancer Patient Chronic Clinical Management Clinical Oncology Clinical Research Colitis Colon Combination immunotherapy Data Development Distant Engineering Foundations Future Generations Genetic Genetic Engineering Genetic Variation Heat-Shock Proteins 70 Human IL8RB gene Immune Immune checkpoint inhibitor Immune response Immunooncology Immunotherapeutic agent Immunotherapy Incidence Individual Inflammasome Inflammatory Innate Immune System Institutional Review Boards Investigation Knock-out Lamina Propria Lead Link Lung Mediating Modality Modeling Mus Mutation Neutrophil Infiltration Nivolumab Organ Outcome PD-1 blockade Pathogenesis Pathology Pathway interactions Patients Pharmacology Plasma Prevalence Protocols documentation Pulmonary Inflammation Quality of life Recurrence Regimen Role Signal Transduction Specimen Steroid Resistance Steroids Structure of parenchyma of lung TLR4 gene Therapeutic Tissue Harvesting Tissues Toxic effect Transgenic Model Transgenic Organisms Tumor Tissue Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy antibody immunotherapy base biomarker development cancer type candidate marker chemokine design immune-related adverse events immunomodulatory therapies improved inhibitor/antagonist insight ipilimumab melanoma neutrophil novel novel therapeutic intervention predictive marker programmed cell death ligand 1 response side effect small molecule inhibitor success treatment strategy tumor tumor DNA tumor ablation

项目摘要

The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncology has resulted in an increased incidence of a variety of immune-related adverse events (irAEs), some of which can have a lasting impact on the lives of our patients. The continued development of adjuvant immunotherapy protocols and more potent immunotherapy combinations such as the ipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs. Despite their growing prevalence, the underlying pathogenesis of individual irAEs is poorly understood and our therapeutic management of these conditions remains crude. Using a genetically engineered model of melanoma, we have found that anti-PD-1 antibody (ab) immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon lamina propria, closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitis and colitis, respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearing mice eliminates the development of these irAEs, suggesting the presence of a tumor-intrinsic pro- inflammatory mechanism. As part of this work, we have recently identified a tumor-intrinsic PD- L1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs including the lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knock- out of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasome suppresses the accumulation of neutrophils in these distant tissues. Based on these findings, we now hypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitor- associated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target for suppressing the development of these irAEs. To address this hypothesis, we have generated a transgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 in the development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will address a potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues and whether a small molecule inhibitor of NLRP3 would be a superior option over steroids for the management of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1 ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoing checkpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if genetic variations of NLRP3 may contribute to the development of these irAEs. Overall, this work will provide unique mechanistic insight into the development of irAEs and identify rational therapeutic strategies and predictive biomarkers for improving the management of patients undergoing immunotherapy.

在临床肿瘤学中，最近的成功和扩展的检查点抑制剂免疫疗法的使用导致各种免疫相关不良事件（iraes）的发生率增加，其中一些这可能会对我们患者的生活产生持久影响。佐剂的持续发展免疫疗法方案和更有效的免疫疗法组合，例如预计ipilimumab/nivolumab方案有望增加这些伊拉斯的发生率和社会影响。尽管越来越流行，但个人伊拉斯的潜在发病机理知之甚少而且我们对这些疾病的治疗管理仍然很粗糙。使用了黑色素瘤的基因工程模型，我们发现抗PD-1抗体（AB）免疫疗法通常会导致肺实质和结肠层的中性粒细胞浸润 PROPIA，与人类检查点抑制剂相关肺炎中指出的病理非常类似和结肠炎。这项工作进一步揭示了抗PD-1 AB的非肿瘤处理小鼠消除了这些伊拉斯的发展，表明存在炎症机制。作为这项工作的一部分，我们最近确定了肿瘤内部的PD- L1：NLRP3：HSP70信号轴，驱动中性粒细胞在远处器官中的积累响应PD-1封锁的肺和结肠。其他研究表明，遗传敲击从肿瘤HSP70表达和NLRP3炎症体的药理抑制抑制中性粒细胞在这些遥远组织中的积累。根据这些发现，我们现在假设肿瘤NLRP3炎性体促进了检查点抑制剂的发展 - 相关的结肠炎和肺炎，NLRP3代表了一个有希望的药理学靶标抑制这些伊拉斯的发展。为了解决这一假设，我们已经产生了转基因黑色素瘤特异性NLRP3 - / - 模型，以检查肿瘤 - 内膜NLRP3的作用检查点抑制剂诱导的结肠炎和肺炎的发展。其他研究将解决在这些遥远的器官组织中Th17分化中，该肿瘤NLRP3途径的潜在作用 NLRP3的小分子抑制剂是否比类固醇是优越的选择正在接受抗PD-1的自毒性黑色素瘤模型中结肠炎和肺炎的治疗 AB免疫疗法。我们将进一步利用正在接受的患者的肿瘤组织和DNA 在主动IRB批准的临床研究中检查点抑制剂免疫疗法，以确定遗传是否遗传 NLRP3的变化可能有助于这些伊拉斯的发展。总体而言，这项工作将提供对伊拉斯发展的独特机械洞察力，并确定理性的治疗策略以及改善接受免疫疗法的患者的治疗的预测生物标志物。