ETIB Clinical Trials

ETIB 临床试验

• 批准号: 9556413
• 负责人: Ronald Gress
• 金额: $ 153.01万
• 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/9556413
• 关键词: Address; Adult; Aftercare; Age-Years; Allogenic; Androgens; Apoptotic; Area; BCL2 gene; Biological Assay; Biopsy; Bone Marrow Transplantation; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Complication; Cytomegalovirus Infections; Data; Data Set; Databases; Dose; Effector Cell; Elderly; Failure; Family; Frequencies; Gaussian model; Graft Rejection; Hematology; Hematopoietic Stem Cell Transplantation; Human; IL7R gene; Immune; Immune system; Immunology; Interleukin-7; Laboratories; Laboratory Finding; Lead; Lung; Lymph; Memory; Multicenter Trials; Multiple Myeloma; Nature; Non-Hodgkin' s Lymphoma; Organ Transplantation; Output; PECAM1 gene; Pathogenesis; Patients; Peripheral; Peripheral Stem Cell Transplantation; Population; Process; Prospective Studies; Recombinants; Regenerative Medicine; Regulatory T-Lymphocyte; Relapse; Research; Signal Transduction; Source; Stem Cell Research; Steroid therapy; T memory cell; T-Lymphocyte; Therapeutic Agents; Thymus Gland; Tissues; Transplantation; base; cancer site; cancer therapy; cell growth; cellular engineering; chemotherapy; chronic graft versus host disease; follow-up; graft vs host disease; leukemia; novel therapeutics; 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 naive 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 delayed pending a source of clinical grade IL-7. We have also initiated a new clinical trial to treat the pulmonary complication of chronic graft versus host disease known as bronchiolitis obliterans.Results were encouraging and led to a national multi-center trial. A new trial has also begun to treat leukemia with myeloablative therapy and assess improvement in immune reconstitution by modulation of thymus function by temporary blockade of androgen signalling. That trial is open and ongoing. 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. We have used cells and tissue biopsies from this trial to prospectively study the pathogenesis of chronic graft-versus host disease and found that it a Type I driven (not Type II as has been thought) process. We are seeking new therapies for this complication of allogeneic transplant based on this new understanding. Therapies associated with this project have expanded through collaboration to include T cell engineering.

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总群体的百分比。由于这种种群转移的程度，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短，一些患者的高级年龄以及我们观察到的最幼稚的T细胞（排序CD31+ CD45RA+ CD4细胞）中TREC频率的下降，这种增强的多样性主要是由于不同的人群扩张，而不是IL-7诱导的胸腺素输出。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，正在解决这种曲目的维修功能重要性，该试验延迟了临床IL-7级来源。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，称为细支气管炎，令人鼓舞并导致了全国性的多中心试验。一项新的试验还开始通过脊髓毛治疗来治疗白血病，并通过通过暂时阻断雄激素信号传导来调节胸腺功能来评估免疫重建的改善。该试验是开放和持续的。在一项涉及无关供体同种异体外周血干细胞移植的试验中，我们开发了与免疫重建有关的实验室值的广泛，临床注释的数据库。该数据集表明，类固醇治疗对T细胞的数量几乎没有立即影响，并证实了我们关于与CMV感染相关的CD8+ T细胞扩展的数据。我们已经使用了该试验中的细胞和组织活检来前瞻性地研究慢性移植物抗宿主疾病的发病机理，并发现它是I型驱动的（不是II型）过程。我们正在基于这种新的理解，为这种同种异体移植的并发症寻求新的疗法。与该项目相关的疗法通过协作扩展，包括T细胞工程。