Prevention of Graft-Versus-Host-Disease in the Era of Adoptive Immunotherapy

项目摘要/摘要 项目：项目3 异基因造血细胞移植(HCT)通常治愈其他致命的白血病。 然而，单独使用免疫抑制药物(IS)的传统T细胞全系HCT通常会因以下原因而复杂化 移植物抗宿主病(GVHD)，这与16%的HCT接受者的死亡率有关。生活质量 患有中度或重度慢性移植物抗宿主病。此外，长期的移植物抗宿主病排除了T细胞的使用 预防或治疗血细胞移植后复发的白血病的免疫疗法或疫苗接种。T细胞耗尽是 对预防移植物抗宿主病有效，但免疫恢复缓慢和机会性高的比率使其复杂化 感染。该项目的目标是开发一种改进的HCT策略，以快速预防GVHD 重建病原体特异性免疫并促进未来的免疫治疗方法以减少 旧病复发。这项研究的最终目的是改善白血病患者的健康和存活率。 为了提高无GVHD、无复发生存(GRFS)，我们开发了两种新的HCT方法：1)外周血 去除干细胞移植物中的原始T细胞的血液干细胞移植(PBSCT)和2) 干细胞输注后3-4天进行PBSCT，然后给予环磷酰胺(移植后； PTCy)。在TND或PTCy的单臂临床试验中，我们观察到慢性 移植物抗宿主病(GVHD)高于接受常规HCT计划的PBSCT受者的一般情况。我们现在在目标1中提出一项 II期随机对照试验(RCT)：PBSCT联合TND或PTCy与PBSCT联合抗胸腺细胞试验 球蛋白(ATG)，后者是一种标准的GVHD预防方法，采用灵活的、挑选赢家的试验设计。 我们的目标是选择一种新的PBSCT策略，以进入第三阶段RCT，该阶段将定义最佳 在最大限度地减少复发、GVHD和对IS的依赖的同时最大化生存的方法。 在HCT后早期提供的T细胞免疫治疗和其他免疫操作具有 有可能减少复发，并将通过鉴定骨髓淋巴细胞特征来实现 预示着旧病复发。令人振奋的新技术，包括单细胞RNA测序(scRNA-seq)和TCR Deep 测序(TCR-SEQ)应有助于这些数据的获取，并将在目标2中进行评估。 具体目标是： 目的1：对急性白血病患者进行II期随机对照试验，比较两种新策略(TND 和PTCy)转变为标准的HCT策略(ATG)，旨在提高无GVHD、无复发的存活率和 避免清髓异基因PBSCT后长时间的IS。 目的2：评价外周血和骨髓免疫细胞的重建和功能 血细胞移植受者的亚群以确定淋巴细胞签名是否与机会性有关 感染或急性髓系白血病复发。

PROJECT SUMMARY/ABSTRACT Project: Project 3 Allogeneic hematopoietic cell transplantation (HCT) is frequently curative for otherwise fatal leukemia. However, conventional T cell-replete HCT, using immunosuppressive drugs (IS) alone, is often complicated by graft-versus-host disease (GVHD), which is associated with mortality in 16% of HCT recipients. Quality-of-life is compromised by moderate or severe chronic GVHD. Moreover, prolonged GVHD precludes the use of T cell immunotherapy or vaccination to prevent or treat leukemia that recurs following HCT. T cell depletion is effective for preventing GVHD, but is complicated by slow immune recovery and high rates of opportunistic infection. The objective of this project is to develop an improved HCT strategy to prevent GVHD, rapidly reconstitute pathogen-specific immunity and facilitate future immunotherapeutic approaches to reduce relapse. The research ultimately aims to improve the health and survival of leukemia patients. To improve GVHD-free, relapse-free survival (GRFS), we developed two new HCT approaches: 1) peripheral blood stem cell transplantation (PBSCT) with depletion of naïve T cells from the stem cell graft (TND) and 2) PBSCT followed by administration of cyclophosphamide 3-4 days after stem cell infusion (post-transplant Cy; PTCy). In single-arm clinical trials of either TND or PTCy, we observed substantially lower rates of chronic GVHD than is usual among recipients of PBSCT on conventional HCT plans. We now propose in Aim 1 a phase II randomized controlled trial (RCT), comparing PBSCT with TND or PTCy to PBSCT with anti-thymocyte globulin (ATG), the latter a standard GVHD prophylaxis approach, using a flexible, pick-the-winner trial design. Our goal is to select one novel PBSCT strategy to advance to a phase III RCT that will define the best approach for maximizing survival while minimizing relapse, GVHD and dependence on IS. T cell immunotherapy and other immune manipulations delivered in the early post-HCT period have the potential to reduce relapse and would be enabled by identification of bone marrow lymphocyte signatures that presage relapse. Exciting new technologies, including single cell RNA sequencing (scRNA-seq) and TCR deep sequencing (TCR-seq) should facilitate the acquisition of these data and will be evaluated in Aim 2. The specific aims are: Aim 1: To conduct a phase II RCT for patients with acute leukemia comparing two novel strategies (TND and PTCy) to a standard HCT strategy (ATG), aiming to improve GVHD-free, relapse-free survival and avoid prolonged IS after myeloablative allogeneic PBSCT. Aim 2: To evaluate reconstitution and function of peripheral blood and bone marrow immune cell subsets in HCT recipients to determine if lymphocyte signatures are associated with opportunistic infection or AML relapse.