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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.

最近检查点抑制剂免疫疗法在临床肿瘤学中的成功和扩大使用