Investigating the Effects of Th2 Modulation on the Generation and Persistence of Tissue Adaptive Immune Memory in Chronic Rhinosinusitis With Nasal Polyposis
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Endotyping nasal response to Mepolizumab
研究概览
简要总结
Chronic rhinosinusitis (CRS) is a condition of persistent sinonasal mucosal inflammation which affects 11.9% of the US population. Mepolizumab is newly approved to treat chronic rhinosinusitis with nasal polyps (CRSwNP, the spaces inside nose and head are swollen and inflamed) and acts booking interleukin-5 (IL-5) a protein implicated in the inflammatory process. We aim to use Single-cell RNA sequencing (RNA-Seq, a method of genetically 'barcoding' cells to allow gene expression to be profiled at the level of individual cells) to study the effects of IL-5 blockade on the generation and maintenance of nasal adaptive immune responses, in CRS subjects.
详细描述
Purpose:
CRS is a poorly understood disease with suboptimal therapeutic strategies and a high disease burden. Adaptive immunity in the form of Th2 polarized T cell responses and B cell IgE class switching, and plasma cell infiltration, are a core component of eosinophilic CRS and asthma, yet our understanding of adaptive immunity in CRS remains limited. Modulating the Th2 response, through IL-5 blockade, leads to mixed results for CRSwNP patients. There are a number of patients who achieve improved asthma control with IL-5 blockade therapies that fail to see the same improvements in their nasal disease, outlining the currently limited understanding of factors involved in disease activity, disease endotypes, and the effects of modulating the Th2 response in this tissue environment. Improved understanding of nasal tissue immunity modulation by IL-5 blockade at a cellular level is an essential step towards appropriate patient selection and development of new targeted therapeutics. Single-cell transcriptomics is powerful tool for characterizing tissue immune landscapes and functional variations, has as yet been poorly utilized beyond studies of nasal epithelium in CRS
Hypothesis
- IL-5 blockade stimulates increased activity of nasal tissue T cells > peripheral blood T cells, and promotes increased tissue T cell Th2 polarization
- IL-5 blockade stimulates increased B cell germinal center activity in nasal secondary and tertiary lymphoid structures, through increased Tfh-B cell interactions and increased maturation to tissue antibody-secreting cells through BLIMP1 upregulation in Germinal Centre B cells.
Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must be >=19 of age at the time of signing the informed consent form.
- •Capable of giving signed informed consent.
- •Treatment group:
- •Bilateral Chronic Rhinosinusitis with Nasal Polyposis and Asthma
- •a. Diagnosis consistent with EPOS 2020 b. Endoscopic Nasal Polyps Score (1-8) c. Asthma diagnosis based on: i. Consistent Clinical symptoms (History of wheeze, cough and breathlessness) ii. Reversible airflow obstruction (Spirometry)
- •Eligibility for Mepolizumab therapy (Canada)
- •On waiting list for surgery with planned wait of >6 months
- •Disease control group:
- •Bilateral Chronic Rhinosinusitis without Nasal Polyposis, (only for the disease control group) oDiagnosis consistent with EPOS 2020
- •Healthy controls:
- •Participants >=19 of age and capable of giving signed informed consent
- •Participants with no history of sinonasal or lower airway disease
排除标准
- •Participants are excluded from the trial if any of the following criteria apply:
- •Women who are pregnant, plan to become pregnant or breastfeed during the trial.
- •Current participation in any other interventional treatment trials.
- •Compliance: is unlikely to comply with trial visits based on investigator judgment.
- •Secondary, or suspected secondary, cause of nasal polyposis:
- •EGPA, positive MPO ANCA or circulating eosinophilia >10% total leukocytes
- •Known or suspected hereditary ciliary dysmotility (e.g: Cystic fibrosis, childhood-onset nasal polyposis)
- •Diagnosed or suspected malignant or premalignant nasal disease (e.g: Schniderian Papilloma, unilateral nasal polyposis)
- •Fungal rhinosinusitis (CT/Histology), positive Aspergillus skin prick testing and/or positive Aspergillus IgE RAST testing.
- •Aspirin Exacerbated Respiratory Disease/Salicylate allergy
- •Known hypersensitivity or significant allergies to monoclonal antibodies.
- •Malignant neoplasm within 5 years (from screening) excluding basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and without metastatic disease for 3 years.
- •A history of a primary immunodeficiency.
- •Active bleeding disorders, and/or inability to support interruption to anticoagulant or anti-platelet therapies for nasal biopsy.
- •Severe nasal deformity precluding endoscopic assessment/biopsy of postnasal space
- •Severe heart failure (New York Heart Association Class IV) or other severe, uncontrolled cardiac disease.
- •Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant.
- •Have an acute or chronic infection (excluding that related to CRS) requiring management as follows:
- •Currently on any treatment for a chronic infection such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria
- •Hospitalisation solely for treatment of proven infection requiring parenteral (IV or IM) antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60 days of Day
- •Proven severe infection requiring outpatient treatment with parenteral (IV or IM) antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60 days of Day
- •Prophylactic anti-infective treatment is allowed.
- •Known positive human immunodeficiency virus (HIV) status.
- •Known positive Hepatitis B (HB) or Hepatitis C status.
- •Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not related to asthma which, in the opinion of the principal investigator, could confound the results of the trial or put the participant at undue risk.
- •Have a planned surgical procedure, laboratory abnormality, or condition that, in the opinion of the principal investigator, makes the participant unsuitable for the trial.
- •Have received any monoclonal antibody therapy ever.
- •Have received any investigational agent (that is not approved for sale in Canada) within 60 days of Day
- •Have previously undergone sinus surgery or nasal polypectomy
- •Previous immunomodulatory therapy (excluding corticosteroids)
- •Healthy controls exclusion criteria
- •Have previously undergone sinus surgery or nasal polypectomy
- •Have received any monoclonal antibody therapy (e.g., dupilumab, mepolizumab, omalizumab)
- •Have known hypersensitivity or significant allergies to monoclonal antibodies
- •Have a positive human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C status
- •Have tumors in the nasal cavity
- •Participants currently participating in other clinical trials
- •Have severe, uncontrolled cardiac disease
- •Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant
- •Have an acute or chronic infection that is not related to chronic rhinosinusitis
研究组 & 干预措施
Treatment
20 subjects with CRSwNP and asthma that will start Mepolizumab treatment
干预措施: Mepolizumab (Drug)
结局指标
主要结局
Endotyping nasal response to Mepolizumab
时间窗: week 30
Clinical response vs standard of care change in degree os eosinophil depletion
Nasal immune endotyping
时间窗: week 30
Comparison of Circulating B cells, Pre-IL-5 subjects, CRSsNP subjects, Healthy controls, Nasal vs NALT
次要结局
未报告次要终点
研究者
Dr. Andrew Thamboo, MD
Clinical Assistant Professor
St. Paul's Sinus Centre