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：
10454406
负责人：
Brent Allen Hanks
金额：
$ 38.68万
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/10454406
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 inhibitor therapy 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.

检查点抑制剂免疫疗法最近在临床肿瘤学中的成功和扩大使用导致各种免疫相关不良事件 (irAE) 的发生率增加，其中一些这会对我们患者的生活产生持久的影响。佐剂的持续发展免疫治疗方案和更有效的免疫治疗组合，例如伊匹单抗/纳武单抗方案预计会增加这些 irAE 的发生率和社会影响。尽管其患病率不断上升，但对个体 irAE 的潜在发病机制仍知之甚少我们对这些病症的治疗管理仍然很粗糙。使用黑色素瘤基因工程模型，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固有层，与人类检查点抑制剂相关肺炎的病理学非常相似和结肠炎。这项工作进一步揭示了抗PD-1抗体治疗非荷瘤患者小鼠消除了这些 irAE 的发展，表明存在肿瘤内在亲炎症机制。作为这项工作的一部分，我们最近发现了一种肿瘤内在的 PD- L1:NLRP3:HSP70 信号轴驱动中性粒细胞在远处器官中的积累，包括肺和结肠对 PD-1 阻断的反应。其他研究表明，基因敲除肿瘤 HSP70 表达和 NLRP3 炎症小体的药理学抑制抑制中性粒细胞在这些远处组织中的积累。基于这些发现，我们现在假设肿瘤 NLRP3 炎症小体促进检查点抑制剂的发展相关的结肠炎和肺炎，NLRP3 代表了一个有前途的药理学靶点抑制这些 irAE 的发展。为了解决这个假设，我们生成了一个转基因黑色素瘤组织特异性 NLRP3-/- 模型，用于检查肿瘤内在 NLRP3 在检查点抑制剂诱发的结肠炎和肺炎的发展。额外的研究将解决该肿瘤 NLRP3 通路在这些远处器官组织中 Th17 分化中的潜在作用， NLRP3 的小分子抑制剂是否是比类固醇更好的选择接受抗 PD-1 治疗的本土黑色素瘤模型中结肠炎和肺炎的治疗 ab免疫治疗。我们将进一步利用从接受手术的患者身上收集的肿瘤组织和DNA 检查点抑制剂免疫疗法在 IRB 批准的一项积极的临床研究中进行，以确定是否遗传 NLRP3 的变异可能有助于这些 irAE 的发生。总的来说，这项工作将提供对 irAE 发展的独特机制洞察并确定合理的治疗策略以及用于改善接受免疫治疗的患者管理的预测生物标志物。