ETIB Clinical Trials

我们对成人免疫重建的研究表明，胸腺生成更新有限的老年患者会出现幼稚T细胞和TCR谱系的严重缺陷并持续存在。为了开发IL-7作为一种潜在的治疗剂来增强这些患者的NAVE群体，我们启动了重组人IL-7(rhIL-7)在人体内应用的第一阶段研究。我们发现，用重组人白介素7隔天治疗两周后，循环中的CD4+和CD8+T细胞的数量显著增加，并在治疗后6到12周持续进行跟踪检测。14，15此外，重组人白介素7治疗不成比例地增加了CCR7+CD27+CD45RA+幼稚和CCR7+CD27+CD45RA-中央记忆细胞，这是成熟TCR池中最多样化的组成部分，而牺牲了CCR7-CD27-CD45RA+/-效应细胞群体。幼稚细胞在CD8+细胞总数中的比例增加了39%。我们进一步证明，IL-7在幼稚T细胞和记忆T细胞中产生延长的细胞扩张期(Ki67+)和抗凋亡因子(Bcl2)的升高，但在效应性T细胞中不产生。这种差异的部分基础是IL-7R(CD127)在效应器T细胞中的相对低表达，特别是CD8效应器。同样，IL-7R低表达的Treg细胞在IL-7治疗开始后，周期细胞的百分比没有出现同样的急剧增加，并且作为总CD4群体的百分比下降。由于这种群体转移的程度，我们假设IL-7将导致CD4+和CD8+T细胞TCR多样性的总体增加。我们对6名受试者在重组人白介素7治疗后第0天和一周(第21天)对分选的CD4和CD8细胞进行光谱分析，评估TCR多样性。其中三名受试者年龄超过60岁，第四名患者在最近的化疗后出现严重的T细胞缺陷。对于每个患者，我们比较了治疗前和治疗后频谱与高斯型正常捐赠者标准的差异。用Wilcoxon配对非参数分析比较了22个BV家系的谱型前后的全球多样性(与正常供者标准的差异)。我们确定，与基线相比，6名受试者中有4名在接受IL-7治疗后，在CD4+、CD8+或这两种T细胞群中，谱系多样性有统计学上的显著增加(P&lt；0.05)。这种幼稚和中央记忆T细胞的扩张和效应细胞的不成比例丢失在CD8人群中尤其明显，在CD8人群中，有5/6的患者有明显的变化或强烈的趋势，增加了谱系多样性。考虑到治疗持续时间较短，一些患者年龄较高，以及我们观察到的最原始T细胞(分类的CD31+CD45RA+CD4细胞)中TREC频率的下降，这种多样性的增强主要是由于不同的种群扩张，而不是IL-7诱导的胸腺输出。因此，我们已经证明，重组人白介素7有可能在幼稚和CM人群中诱导胸腺非依赖性T细胞的生长，并增强外周T细胞群体中的谱系多样性。目前正在进行的一项新的临床试验正在研究这一修复谱系是否具有重要的功能，目前正在招募患者。我们还启动了一项新的临床试验，以治疗慢性移植物抗宿主病的肺部并发症，即闭塞性细支气管炎。初步结果令人鼓舞，这项研究仍然开放和积极。一项新的试验也开始用清髓疗法治疗白血病，并通过调节胸腺功能来评估免疫重建的改善。在一项涉及无关供者异基因外周血干细胞移植的试验中，我们开发了一个广泛的、带有临床注释的与免疫重建相关的实验室数值数据库。这一数据集表明，类固醇治疗对T细胞数量几乎没有直接影响，并证实了我们关于CD8+T细胞与CMV感染相关的扩张的数据。类固醇对T细胞亚群分布的定性影响正在研究中。

Our studies of adult immune reconstitution have demonstrated that severe deficits in naive T cells and TCR repertoire develop and persist in older patients with limited renewal of thymopoiesis. In order to develop IL-7 as a potential therapeutic agent to enhance nave populations in these patients, we initiated the first phase I study of recombinant human IL-7 (rhIL-7) administration in humans. We demonstrated that two weeks of alternate day treatment with rhIL-7 produced a marked dose-dependent increase in the numbers of circulating CD4+ and CD8+ T cells that persisted in follow-up assays at 6 to 12 weeks post treatment.14,15 Furthermore, rhIL-7 therapy disproportionately increased CCR7+CD27+CD45RA+ naive and CCR7+CD27+CD45RA- central memory cells, which represent the most diverse components of the mature TCR pool, at the expense of the CCR7-CD27-CD45RA+/- effector populations. The proportion of naive cells in the total CD8+ population increased by as much as 39%. We further documented that IL-7 produced a prolonged period of cellular expansion (Ki67+ ) and elevation of anti-apoptotic factors (Bcl-2) in naive and memory T cells, but not in effector T cells. Part of the basis for this disparity is the relatively low expression of the IL-7R(CD127) in effector T cells, particularly CD8 effectors. Similarly Treg cells, which have low expression of IL-7R, did not show the same sharp increase in the percentage of cells in cycle following initiation of IL-7 therapy and declined as a percentage of the total CD4 population. Because of the extent of this population shift, we hypothesized that IL-7 would lead to an overall increase in TCR diversity in CD4+ and CD8+ T-cells. We assessed TCR diversity using spectratype analysis on sorted CD4 and CD8 populations at day 0 and one week after rhIL-7 therapy (day 21) in six subjects. Three of these subjects were over 60 years of age, and a fourth patient was severely T cell deficient following recent chemotherapy. For each patient, we compared pre- and post-therapy spectratype divergence from a Gaussian-like normal donor standard. The global diversity (divergence from a normal donor standard in each of 22 BV families) of pre and post spectratypes was compared by Wilcoxon paired non-parametric analysis. We determined that 4 of the 6 subjects had a statistically significant increase (P < .05) in repertoire diversity following IL-7 treatment, as compared to baseline, in either the CD4+, CD8+, or both T-cell populations. This expansion of nave and central memory T cells and the disproportional loss in effector cells was particularly evident in CD8 populations in which 5/6 patients had either a significant shift or a strong trend toward increased repertoire diversity. Given the short duration of therapy, the advanced ages of some patients, and the PCR-assessed decline in the frequency of TREC in even the most nave T cells (sorted CD31+CD45RA+ CD4 cells) that we observed, this enhancement in diversity was due primarily to differential population expansion, not IL-7 induced thymic output. We have thus shown that rhIL-7 has the potential to induce thymic-independent T-cell growth in naive and CM populations and enhance repertoire diversity in peripheral T-cell populations. Whether this repair of repertoire is of functional importance is being addressed in a new clinical trial which is now accruing patients. We have also initiated a new clinical trial to treat the pulmonary complication of chronic graft versus host disease known as bronchiolitis obliterans. Preliminary results are encouraging and the study remains open and active. A new trial has also begun to treat leukemia with myeloablative therapy and assess improvement in immune reconstitution by modulation of thymus function. In a trial involving unrelated donor allogeneic peripheral blood stem cell transplantation, we have developed an extensive, clinically annotated data base of laboratory values relevant to immune reconstitution. This data set has shown that steroid therapy has little immediate effect on T cell numbers, and confirms our data on expansion of CD8+ T cells associated with CMV infection. The qualitative effect of steroids on T cell subset distribution is under investigation.