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.

我们对成人免疫重建的研究表明，幼稚T细胞和TCR库的严重缺陷在胸腺生成更新有限的老年患者中发展并持续存在。为了开发IL-7作为一种潜在的治疗剂，以提高这些患者的初发人群，我们开始了第一个I期研究重组人IL-7（rhIL-7）的管理在人类。我们证明，rhIL-7隔日治疗两周可使循环中的CD 4+和CD 8 + T细胞数量呈剂量依赖性显著增加，并在治疗后6至12周的随访试验中持续存在。14，15此外，rhIL-7治疗不成比例地增加了CCR 7 + CD 27 + CD 45 RA+幼稚和CCR 7 + CD 27 + CD 45 RA-中枢记忆细胞，其代表成熟TCR库的最多样化的组分，以CCR 7-CD 27-CD 45 RA +/-效应物群体为代价。幼稚细胞在总CD 8+群体中的比例增加了多达39%。我们进一步证明，IL-7产生了一个长期的细胞扩增（Ki 67+）和抗凋亡因子（Bcl-2）在幼稚和记忆T细胞的升高，但不是在效应T细胞。这种差异的部分基础是效应T细胞，特别是CD 8效应细胞中IL-7 R（CD 127）的表达相对较低。类似地，具有低IL-7 R表达的Treg细胞在IL-7治疗开始后在周期中的细胞百分比没有显示出相同的急剧增加，并且作为总CD 4群体的百分比下降。我们在6名受试者中，在rhIL-7治疗后0天和1周（第21天）对分选的CD 4和CD 8群体使用谱型分析评估TCR多样性。这些受试者中有三名年龄超过60岁，第四名患者在最近的化疗后严重缺乏T细胞。对于每一个病人，我们比较了治疗前和治疗后的光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光谱分析前后的总体多样性（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，IL-7治疗后，6例受试者中有4例的CD 4+、CD 8+或两种T细胞群的库多样性出现统计学显著性增加（P 0.05）。这种原始和中央记忆T细胞的扩增以及效应细胞的不成比例损失在CD 8群体中特别明显，其中5/6的患者具有显著的转变或向增加的库多样性的强烈趋势。考虑到治疗持续时间短，一些患者年龄大，以及我们观察到的即使是最原始的T细胞（分选的CD 31 + CD 45 RA + CD 4细胞）中PCR评估的TREC频率下降，这种多样性的增强主要是由于差异性群体扩增，而不是IL-7诱导的胸腺输出。因此，我们已经表明，rhIL-7有可能诱导胸腺非依赖性T细胞生长的幼稚和CM人口和提高外周T细胞群的库多样性。一项新的临床试验正在研究这种修复是否具有功能重要性，该临床试验目前正在招募患者，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（称为闭塞性细支气管炎）的肺部并发症。 初步结果令人鼓舞，研究仍在进行中。 一项新的试验也开始用清髓性疗法治疗白血病，并评估通过调节胸腺功能来改善免疫重建。