ETIB Clinical Trials

我们对成人免疫重建的研究表明，在胸腺功能更新有限的老年患者中，幼稚T细胞和TCR库的严重缺陷会发展并持续存在。为了开发IL-7作为一种潜在的治疗药物，以增加这些患者的中性人群，我们启动了重组人IL-7 （rhIL-7）在人体内给药的第一阶段研究。我们证明，用rhIL-7隔天治疗两周后，循环CD4+和CD8+ T细胞的数量出现了明显的剂量依赖性增加，这种增加在治疗后6至12周的随访分析中持续存在此外，rhIL-7治疗不成比例地增加了CCR7+CD27+CD45RA+幼稚和CCR7+CD27+CD45RA-中枢记忆细胞，这些细胞代表了成熟TCR池中最多样化的组成部分，以牺牲CCR7-CD27-CD45RA+/-效应细胞群为代价。初始细胞在CD8+总细胞群中的比例增加了39%。我们进一步证明，IL-7在幼稚T细胞和记忆T细胞中产生长时间的细胞扩增（Ki67+）和抗凋亡因子（Bcl-2）的升高，但在效应T细胞中没有。造成这种差异的部分原因是效应T细胞，特别是CD8效应T细胞中IL-7R（CD127）的表达相对较低。同样，IL-7R低表达的Treg细胞，在开始IL-7治疗后，在周期内的细胞百分比没有出现同样的急剧增加，并且在总CD4群体中所占的百分比有所下降。由于这种群体转移的程度，我们假设IL-7会导致CD4+和CD8+ t细胞中TCR多样性的总体增加。我们通过对6名受试者在rhIL-7治疗后第0天和第21天对CD4和CD8人群进行分类的谱型分析来评估TCR多样性。其中三名患者年龄超过60岁，第四名患者在最近的化疗后出现了严重的T细胞缺陷。对于每个患者，我们比较了治疗前和治疗后的谱型偏离高斯样正常供体标准。通过Wilcoxon配对非参数分析比较了前后谱型的全球多样性（22个BV家族中每个家族与正常供体标准的差异）。我们确定，与基线相比，在IL-7治疗后，6名受试者中有4名在CD4+、CD8+或两种t细胞群中，CD4+、CD8+或两种t细胞群的多样性有统计学意义上的显著增加（P < 0.05）。中记忆T细胞和中枢记忆T细胞的扩张以及效应细胞的不成比例的损失在CD8人群中尤为明显，其中5/6的患者要么有显著的转变，要么有强烈的趋势，即曲目多样性增加。鉴于我们观察到的治疗时间短，一些患者年龄大，以及pcr评估的即使是最原始的T细胞（分类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群体扩张，而不是IL-7诱导的胸腺输出。因此，我们已经证明，rhIL-7有可能在幼稚和CM群体中诱导胸腺非依赖性t细胞生长，并增强外周t细胞群体的库多样性。这种修复功能是否具有重要的功能，目前正在进行一项新的临床试验，该试验正在积累患者。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，这项研究仍然是开放和积极的。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。

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.