Abatacept for the treatment of Common Variable Immunodeficiency with Interstitial Lung Disease (ABCVILD) IND #152820 9/2/20

常见变异性免疫缺陷（CVID）影响美国约10，000人， 是由一系列不断扩大的遗传病变引起的它是由国际共识标准定义的， 总结为婴儿期后出现的B细胞功能丧失，伴或不伴 自身免疫或淋巴增生并发症。间质性肺疾病的一种特殊形式的发展- 一种称为肉芽肿性淋巴细胞间质性肺疾病（GLILD）的疾病在CVID中尤其成问题 因为它相对常见，与显著的死亡率和发病率相关，并且对以下方面的需求未得到满足： 适当的治疗。我们发现生物药物阿巴西普对逆转严重的， 在一个小系列的CVID患者中经常出现难治性GLILD。阿巴西普是一种重组融合蛋白， 穿孔CTLA-4（细胞毒性T淋巴细胞相关蛋白4），其通过结合 CD 80/CD 86，从而阻止CD 28接合。我们的研究结果表明阿巴西普是一种有效的- CVID中GLILD的有效治疗。然而，需要严格的临床试验来前瞻性地定义风险 和阿巴西普作为GLILD治疗的益处。 为了填补这一关键空白，我们设计了ABCVILD试验。在这个试验中，我们计划用两种方法治疗- CEBO或阿巴西普。在为期6个月的盲态治疗期后，患者将 进入为期六个月的开放标签阶段，在此期间他们将开始或继续阿巴西普。根据我们的临床 根据迄今为止的经验，我们假设6个月的阿巴西普治疗（与安慰剂相比）将在临床上 改善CVID基因型间的GLILD（通过客观和QOL指标评估）并改善sCD 25 和其他T细胞活化的探索性生物标志物。我们将通过追求以下目标来检验这一假设： 目的1：确定阿巴西普治疗6个月后GLILD的应答率（与安慰剂相比）。 我们对ABCVILD试验的读数包括胸部CT扫描的定量评估，肺功能 测试，生活质量的措施，和无辐射措施129毫米磁共振成像（MRI）。 目的2：确定基因型和/或肺组织学是否可预测GLILD对阿巴西普的反应性 疗法由于CD 4 + T细胞通常是GLILD和T滤泡辅助细胞（Tfh）中最突出的浸润细胞， 细胞实验显示对CD 28/CTLA 4操纵敏感，我们假设， GLILD在很大程度上是Tfh细胞的疾病，并且这种反应性将与病变中的这些细胞相关。 目的3：确定sCD 25、阿巴西普药代动力学或T细胞活性的探索性生物标志物的效用。 用于预测对治疗的反应。我们将连续评估sCD 25，各种探索性生物标志物， 阿巴西普水平，以测试每一个的预测值，了解我们的适应性给药方案的影响， 这些参数，并进一步测试我们的假设，GLILD是不适当的T细胞活化的结果， CVID患者的治疗。

Common variable immunodeficiency (CVID) affects approximately 10,000 people in the USA and is caused by an expanding array of genetic lesions. It is defined by international consensus criteria that may be summarized as loss of B cell function developing after infancy with or without a well-described constellation of autoimmune or lymphoproliferative complications. The development of a distinctive form of interstitial lung dis- ease, termed granulomatous-lymphocytic interstitial lung disease (GLILD), is particularly problematic in CVID because it is relatively common, associated with significant mortality and morbidity, and has an unmet need for adequate treatments. We found that the biologic drug abatacept showed good efficacy for reversal of severe, often refractory GLILD in a small series of patients with CVID. Abatacept is a recombinant fusion protein incor- porating CTLA-4 (cytotoxic T lymphocyte–associated protein 4) that blocks T cell activation by binding to CD80/CD86, thereby preventing CD28 engagement. Our findings suggest that abatacept would be an effec- tive therapy for GLILD in CVID. However, rigorous clinical trials are needed to prospectively define the risks and benefits of abatacept as a therapy for GLILD. To fill this critical gap, we have designed the ABCVILD trial. In this trial, we plan to treat with either pla- cebo or abatacept in a double-blinded fashion. Following a six-month blinded treatment phase, patients will enter a six-month open-label phase in which they will start or continue abatacept. On the basis of our clinical experience to date, we hypothesize that 6 months of abatacept therapy (compared to placebo) will clinically improve GLILD (as assessed by objective and QOL measures) across CVID genotypes and improve sCD25 and other exploratory biomarkers of T cell activation. We will test this hypothesis by pursuing these aims: Aim 1: Determine the response rate of GLILD after six months of abatacept therapy (versus placebo). Our readouts for the ABCVILD trial include quantitative assessment of chest CT scans, pulmonary function tests, quality of life measures, and radiation-free measure 129Xe magnetic resonance image (MRI). Aim 2: Determine whether genotype and/or lung histology predict GLILD responsiveness to abatacept therapy. As CD4+ T cells are often the most prominent infiltrating cells in GLILD and T follicular helper (Tfh) cells have been shown experimentally to be sensitive to CD28/CTLA4 manipulation, we hypothesize that GLILD is largely a disease of Tfh cells and that responsiveness will correlate with these cells in lesions. Aim 3: Define the utility of sCD25, abatacept pharmacokinetics, or exploratory biomarkers of T cell acti- vation for predicting response to therapy. We will serially assess sCD25, various exploratory biomarkers, and abatacept levels to test the predictive value of each, understand the effects of our adaptive dosing regimen on these parameters, and further test our hypothesize that GLILD is a consequence of inappropriate T cell activa- tion in patients with CVID.