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

项目总结/摘要 项目：项目3 异基因造血细胞移植（HCT）通常可以治愈致命的白血病。 然而，单独使用免疫抑制药物（IS）的常规T细胞充满HCT通常因以下因素而复杂化： 移植物抗宿主病（GVHD），其与16%的HCT接受者的死亡率相关。生活质量 受到中度或重度慢性GVHD的影响。此外，长期的GVHD排除了T细胞的使用。 免疫疗法或疫苗接种以预防或治疗HCT后复发白血病。T细胞减少是 有效地预防GVHD，但由于免疫恢复缓慢和机会性移植的高发生率而变得复杂。 感染本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，并促进未来的免疫方法，以减少 复发这项研究的最终目的是改善白血病患者的健康和生存。 为了提高无GVHD、无复发生存率（GRFS），我们开发了两种新的HCT方法：1）外周血 血液干细胞移植（PBSCT），从干细胞移植物（TND）中去除幼稚T细胞，以及2） 干细胞输注后3-4天（移植后Cy; PTCy）。在TND或PTCy的单组临床试验中，我们观察到慢性 GVHD比常规HCT计划的PBSCT接受者中常见的GVHD。我们现在在目标1a中提出 II期随机对照试验（RCT），比较PBSCT联合TND或PTCy与PBSCT联合抗胸腺细胞 球蛋白（ATG），后者是一种标准的GVHD预防方法，使用灵活的，挑选赢家的试验设计。 我们的目标是选择一种新的PBSCT策略，以推进III期RCT，确定最佳的 最大限度地提高生存率，同时最大限度地减少复发，GVHD和对IS的依赖。 在HCT后早期提供的T细胞免疫疗法和其他免疫操作具有 减少复发的潜力，并将通过鉴定骨髓淋巴细胞特征来实现， 预示着复发令人兴奋的新技术，包括单细胞RNA测序（scRNA-seq）和TCR deep TCR-seq测序应有助于获得这些数据，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）与标准HCT策略（ATG）相比较，旨在改善无GVHD、无复发生存期， 避免清髓性异基因PBSCT后IS延长。 目的2：评价外周血和骨髓免疫细胞的重建和功能 HCT接受者中的淋巴细胞亚群，以确定淋巴细胞特征是否与机会性 感染或AML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.