ETIB Clinical Trials

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。我们发现，rhIL-7有可能诱导幼稚和CM人群中的胸腺非依赖性T细胞扩增，并增强外周T细胞群的库多样性。这种库的修复是否具有功能重要性正在一项新的临床试验中得到解决，该临床试验不再推迟，等待临床级IL-7的来源。已经确定了一个新的来源，正在编写一份新的研究报告，最后草稿即将完成。我们还开始了一项临床试验，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，并导致了一个国家多中心试验。总之，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。一项用清髓性治疗白血病并评估通过暂时阻断雄激素信号传导调节胸腺功能改善免疫重建的试验已完成，实验室结果正在研究中。在一项涉及无关供体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、临床注释的免疫重建相关实验室值数据库。该数据集表明，类固醇治疗对T细胞数量几乎没有直接影响，并证实了我们关于与CMV感染相关的CD 8 + T细胞扩增的数据。我们使用本试验的细胞和组织活检前瞻性研究了慢性移植物抗宿主病的发病机制，发现其为I型驱动（而非认为的II型）过程。这些结果现已公布。基于这种新的认识，我们正在寻求同种异体移植并发症的新疗法。在这一点上，似乎引入这种治疗可能会等待批准的其他适应症的药物。在另一项评估移植期间对造血干细胞隔室成像的可行性的试验中，发现这种成像是可行的并且也是可量化的，使得对辐射损伤的设置的适用性是可能的。也就是说，这种损伤的受试者可以被鉴定为需要或不需要造血干细胞拯救的干预。我们获得了IL-7的新来源。先前的研究显示了增强的免疫重建，令人惊讶的发现是T细胞库的再多样化，而不涉及更新的胸腺功能。下一步是研究更新的库是否会导致更好的T细胞介导的免疫应答。然后，编写临床方案以评估对含有和不含IL-7的疫苗的反应。该研究报告已编写完毕，正在审查中。

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.