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

过继免疫疗法时代预防移植物抗宿主病

• 批准号: 10412941
• 负责人: Marie Bleakley
• 金额: $ 88.5万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-28 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412941
• 关键词: Acute; Acute leukemia; Address; Adoptive Immunotherapy; Adult; Allogeneic Bone Marrow Transplantation; Allogenic; Antithymoglobulin; Blood; Bone Marrow; CD34 gene; Cells; Cessation of life; Characteristics; Child; Clinical Trials; Cyclophosphamide; Cyclosporine; Data; Dependence; Development; Dose; Excision; FOXP3 gene; Future; Globulins; Goals; HLA Antigens; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Infusion procedures; Laboratory Study; Lymphocyte; Memory; Methods; Methotrexate; Minor Histocompatibility Antigens; Morbidity - disease rate; Mus; Opportunistic Infections; Outcome; Patients; Pattern; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Pharmacology; Phase; Prevention; Prophylactic treatment; Quality of life; RNA; Randomized; Randomized Controlled Trials; Recovery; Recurrence; Regimen; Regulatory T-Lymphocyte; Relapse; Research; Residual state; Resistance; SELL gene; Site; T cell therapy; T memory cell; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; Universities; Vaccination; adult leukemia; aldehyde dehydrogenases; arm; base; chronic graft versus host disease; clinical practice; conditioning; data acquisition; deep sequencing; disability; disorder prevention; first-in-human; flexibility; follow-up; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; high risk; immune function; immune reconstitution; improved; in vivo; leukemia; leukemia relapse; mortality; mycophenolate mofetil; new technology; novel; novel strategies; pathogen; peripheral blood; phase II trial; post-transplant; preservation; prevent; reconstitution; single-cell RNA sequencing; stem cells; thymocyte; trial comparing; trial design

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.

项目摘要/摘要 项目：项目3 同种异体造血细胞移植（HCT）经常治愈其他致命性白血病。 但是，仅使用免疫抑制药物（IS）的常规T细胞复制HCT通常会因 移植物与宿主病（GVHD），与16％的HCT接受者有关。生活质量 受中度或严重的慢性GVHD损害。此外，长时间的GVHD排除了T细胞的使用 免疫疗法或疫苗可预防或治疗HCT后复发的白血病。 T细胞耗竭是 有效预防GVHD，但由于免疫恢复缓慢和机会率很高而变得复杂 感染。该项目的目的是制定改进的HCT策略以防止GVHD，迅速 重建病原体特异性免疫学并促进未来的免疫治疗方法来减少 复发。该研究最终旨在改善白血病患者的健康和生存。 为了提高无GVHD，无继电器生存（GRF），我们开发了两种新的HCT方法：1）外围 血管细胞移植（PBSCT），从干细胞移植（TND）和2的幼稚T细胞耗竭的血管细胞移植（PBSCT）和2） PBSCT，然后在干细胞输注后3-4天（移植后CY； ptcy）。在TND或PTCY的单臂临床试验中，我们观察到慢性的速率大大降低 GVHD比通常在常规HCT计划中的PBSCT接收者中的GVHD。我们现在提出AIM 1 A II期随机对照试验（RCT），将PBSCT与TND或PTCY与抗胸腺细胞进行比较 Globulin（ATG），后者采用灵活的冠军试验设计，是标准GVHD预防方法。 我们的目标是选择一种新颖的PBSCT策略，以推进将定义最佳的III阶段RCT 最大化生存的方法，同时最大程度地减少退休，GVHD和对IS的依赖。 T细胞免疫疗法和在HCT初期早期进行的其他免疫操纵具有 减少继电器的潜力，并通过识别骨髓淋巴细胞特征来实现 预售继电器。令人兴奋的新技术，包括单细胞RNA测序（SCRNA-SEQ）和TCR Deep 测序（TCR-SEQ）应促进这些数据的获取，并将在AIM 2中进行评估。 具体目的是： 目的1：为急性白血病患者进行II期RCT，比较两种新型策略（TND） 和PTCY）达到标准HCT策略（ATG），旨在提高无GVHD，无继电器生存和 避免长时间是在髓质的同种异体PBSCT之后。 目的2：评估外周血和骨髓免疫核管的重构和功能 HCT接受者中的子集以确定淋巴细胞特征是否与机会性有关 感染或AML继电器。