ETIB Clinical Trials

ETIB 临床试验

• 批准号: 8552903
• 负责人: Ronald Gress
• 金额: $ 257.52万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552903
• 关键词: Address; Adult; Age-Years; Apoptotic; Area; Biological Assay; Bone Marrow Transplantation; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Separation; Cells; Clinical Research; Clinical Trials; Complication; Dose; Effector Cell; Elderly; Failure; Family; Frequencies; Graft Rejection; Hematology; Hematopoietic Stem Cell Transplantation; Human; IL7R gene; Immune; Immune system; Interleukin-7; Laboratory Finding; Lead; Lung; Lymph; Memory; Multiple Myeloma; Nature; Non-Hodgkin' s Lymphoma; Organ Transplantation; Output; PECAM1 gene; Patients; Peripheral; Population; Recombinants; Regenerative Medicine; Regulatory T-Lymphocyte; Relapse; Research; Sorting - Cell Movement; Stem Cell Research; T memory cell; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; Therapeutic Agents; Thymus Gland; Transplantation Immunology; base; cancer site; cancer therapy; cell growth; chemotherapy; chronic graft versus host disease; follow-up; graft vs host disease; leukemia; older patient; phase 1 study; reconstitution; repaired; therapy duration; treatment duration; trend; tumor

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.

我们对成人免疫重构的研究表明，胸腺胰岛素更新有限的老年患者的幼稚T细胞和TCR曲目的严重缺陷会出现并持续存在。为了开发IL-7作为一种潜在的治疗剂来增强这些患者的中殿种群，我们启动了人类重组人IL-7（RHIL-7）给药的第一阶段研究。 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成熟TCR池的最多样化的组成部分，以CCR7-CD27-CD45RA +/-效应人群为代价。总CD8+种群中幼稚细胞的比例增加了39％。我们进一步证明，IL-7在天真和记忆T细胞中产生了长时间的细胞膨胀（Ki67+）和抗凋亡因子（BCL-2）的升高，但没有作用T细胞。这种差异的一部分是效应T细胞（尤其是CD8效应子）中IL-7R（CD127）的表达相对较低。同样，IL-7R表达较低的Treg细胞在开始IL-7治疗后周期中的细胞百分比也没有显示出同样的急剧增加，并且占CD4总人群总数的百分比。因为该人群的程度转移程度，我们假设IL-7会导致CD4+ CD4+ CD8+ T-Cells TCR多样性的总体增加。我们在第0天和RHIL-7治疗后一周（第21天）对六个受试者进行了分类的CD4和CD8种群的频谱分析评估了TCR多样性。这些受试者中有三个年龄超过60岁，最近的化疗后，第四例患者严重缺乏T细胞。对于每个患者，我们比较了疗法前后的频谱谱型与高斯样供体标准的差异。通过Wilcoxon配对的非参数分析比较了频谱前后的全球多样性（与22 BV家族中的正常供体标准的差异（与正常供体标准的差异）。我们确定，与基线相比，在CD4+，CD8+或两个T细胞群体中，这6名受试者中有4个在IL-7处理后的曲目多样性中具有统计学显着的增加（P <.05）。在CD8种群中，中殿和中央记忆T细胞的扩展以及效应细胞中的不良损失尤为明显，在CD8种群中，有5/6例患者的变化很大，或者朝着增加曲目多样性的趋势有很大的变化或强烈的趋势。鉴于治疗的持续时间较短，一些患者的高级年龄以及我们观察到的最中殿T细胞（排序的CD31+ CD45RA+ CD4细胞）中TREC频率的下降，这种增强的多样性的增强主要是由于不同的人群扩张，而不是IL-7诱导的胸腺触发输出。因此，我们已经表明，RHIL-7具有诱导胸腺和CM种群中胸腺独立的T细胞生长的潜力，并增强了周围T细胞种群中的曲目多样性。在一项新的临床试验中，该曲目的修复是否具有功能重要性，该试验正在累积患者。我们还开始了一项新的临床试验，以治疗慢性移植物与宿主疾病的肺部并发症，而宿主疾病被称为细支气管炎的肺炎。 初步结果令人鼓舞，研究仍然开放和活跃。 一项新的试验还开始通过髓局治疗治疗白血病，并通过调节胸腺功能来评估免疫重建的改善。