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

共同变量免疫缺陷(CVID)在美国影响着大约10,000人，是 是由一系列不断扩大的基因损伤引起的。它由国际共识标准来定义，这些标准可能是 总结为在婴儿期后发生的B细胞功能丧失，无论是否有一个描述良好的 自身免疫性或淋巴增生性并发症。一种独特形式的间质性肺疾病的发展。 EASE被称为肉芽肿-淋巴细胞性间质性肺病(GLILD)，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有关，并且有未得到满足的需求 适当的治疗。我们发现生物药物阿巴塔塞特对重症急性呼吸窘迫综合征有良好的逆转作用， 在少数CVID患者中经常出现难治性GLILD。Abatacept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)，通过结合阻止T细胞激活 CD80/CD86，从而阻止CD28结合。我们的研究结果表明，阿巴塔塞特将是一种有效的- 脑血管病合并GLILD的保守治疗。然而，需要严格的临床试验来前瞻性地确定风险。 以及作为GLILD治疗方法的Abatacept的益处。 为了填补这一关键空白，我们设计了ABCVILD试验。在这项试验中，我们计划用两种方案中的任何一种- Cebo或abatacept以双盲方式。在为期六个月的盲目治疗阶段之后，患者将 进入为期六个月的开放标签阶段，在此阶段，他们将开始或继续戒烟。在我们临床的基础上 到目前为止的经验，我们假设6个月的戒毒治疗(与安慰剂相比)将在临床上起作用。 改善跨CVID基因型别的GLILD(通过客观和QOL测量进行评估)，并改善sCD25 以及其他T细胞激活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：测定停药6个月后GLILD的有效率(与安慰剂对照)。 我们的ABCVILD试验读数包括胸部CT扫描、肺功能的定量评估 测试、生活质量测量和无辐射测量129Xe磁共振成像(MRI)。 目的2：确定基因和/或肺组织学是否能预测GLILD对阿巴贝特的反应性 心理治疗。由于CD4+T细胞通常是GLILD和T滤泡辅助细胞(TFH)中最突出的浸润性细胞 实验表明细胞对CD28/CTLA4的操纵很敏感，我们假设 GLILD在很大程度上是一种TFH细胞的疾病，这种反应将与病变中的这些细胞相关。 目的3：明确sCD25、abatacept药代动力学或T细胞活性的探索性生物标记物的用途。 用于预测治疗反应的创新。我们将连续评估CD25、各种探索性生物标志物和 Abatacept水平以测试每个水平的预测价值，了解我们的适应性给药方案对 这些参数，并进一步验证了我们的假设，即GLILD是不适当的T细胞激活的结果。 血管紧张素转换酶在CVID患者中的应用。

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.