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，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细胞的扩张，并增强外周T细胞群体中的谱系多样性。在一项新的临床试验中，正在研究这种谱系的修复是否具有功能重要性，该试验不再被推迟，以等待临床分级IL-7的来源。已经确定了一个新的来源，正在编写一项新的研究报告，最后草案即将完成。我们还启动了一项临床试验，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。结果令人鼓舞，并导致了一项全国性的多中心试验。总而言之，这些结果改变了同种异体移植肺部并发症患者的一般护理。一项用清髓疗法治疗白血病的试验已经完成，并评估了通过暂时阻断雄激素信号调节胸腺功能来改善免疫重建的情况，实验室结果正在研究中。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。我们使用这项试验的细胞和组织活检来前瞻性地研究慢性移植物抗宿主病的发病机制，并发现它是一个I型驱动的过程(而不是一直认为的II型)。这些结果现已发表。基于这一新认识，我们正在寻找治疗同种异体移植并发症的新方法。在这一点上，似乎这种疗法的引入可能会等待此类药物对其他适应症的批准。在另一项评估植入期间对造血干细胞室进行成像的可行性的试验中，发现这种成像是可行的，也是可量化的，因此可能适用于辐射损伤的环境。也就是说，这种损伤的受试者可能被确定为需要进行造血干细胞救援的干预。我们已经获得了一种新的IL-7来源。先前的研究显示了免疫重建的增强，令人惊讶的发现是T细胞谱系的再多样化而不涉及胸腺功能的更新。下一步是研究更新的曲目是否会导致更好的T细胞介导的免疫反应。因此，临床方案是为了评估使用和不使用IL-7的疫苗的反应。这项研究已经撰写完毕，正在进行审查。

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 showed that rhIL-7 has the potential to induce thymic-independent T-cell expansion 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 no longer delayed pending a source of clinical grade IL-7. A new source has been identified and a new study is being written with near completion of the final draft. We also initiated a 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. Together, the results have changed the general care of patients with this pulmonary complication of allogeneic transplant. A trial treating leukemia with myeloablative therapy and assessing improvement in immune reconstitution by modulation of thymus function by temporary blockade of androgen signaling is completed with lab results under study. 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. These results are now published. We are seeking new therapies for this complication of allogeneic transplant based on this new understanding. At this point it appears that introduction of such therapy may await approval of such agents for other indications. In another trial assessing the feasibility of imaging the hematopoietic stem cell compartment during engraftment, it was found that such imaging is feasible and also quantifiable, so that applicability to settings of radiation injury may be possible. That is, subjects of such injury may be identified as needing intervention with hematopoietic stem cell rescue or not. We have gained access to a new source for IL-7. The previous study showed enhanced immune reconstitution with the surprising finding of re-diversification of the T cell repertoire without involvement of renewed thymus function. The next step is to investigate whether that renewed repertoire results in better T cell mediated immune response. The clinical protocol, then, is written to assess response to vaccines with and without IL-7. The study is written and under review.