Naive T cell depletion to prevent graft-versus-host disease

去除幼稚 T 细胞以预防移植物抗宿主病

基本信息

批准号：
9067516
负责人：
Marie Bleakley
金额：
$ 53.96万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067516
关键词：
Acute Graft Versus Host Disease Acute leukemia Adrenal Cortex Hormones Alloantigen Allogenic Antigens Area Avidity CD34 gene CD8B1 gene CSF3 gene Cause of Death Cells Chronic Clinical Clinical Trials Competence Complement Cytotoxic T-Lymphocytes Data Disease Employee Strikes Engraftment Ensure Environment Exhibits Exposure to Future Genetic Grant Histocompatibility Human Human Herpesvirus 4 Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Incidence Infection Inflammation Intervention Intestines Laboratory Study Life Lymphocyte Subset Major Histocompatibility Complex Malignant - descriptor Mediating Medical Memory Methods Methotrexate Microspheres Minor Modeling Morbidity - disease rate Non-Malignant Opportunistic Infections Pathogenesis Patients Peripheral Blood Stem Cell Pharmaceutical Preparations Phase II Clinical Trials Phenotype Procedures Property Quality of life Recovery Recurrence Regimen Regulatory T-Lymphocyte Relapse Research Personnel SELL gene Severities Specificity Stem cells Steroids Symptoms Syndrome T cell response T memory cell T-Cell Activation T-Cell Depletion T-Cell Receptor T-Lymphocyte Tacrolimus Testing Translating Transplantation Vaccination Vent bacterial H antigen base cell injury chronic graft versus host disease conditioning disability disorder control experience gastrointestinal gastrointestinal symptom graft vs host disease hematopoietic cell transplantation human data illness length improved insight leukemia mortality mouse model novel strategies pathogen preclinical study prevent public health relevance reconstitution response

项目摘要

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (HCT) is frequently curative for many otherwise fatal malignant and nonmalignant diseases. However, conventional T cell-replete HCT using pharmacological immunosuppression alone is often complicated by graft versus host disease (GVHD). Mortality attributed to GVHD occurs in 16% of HCT recipients and quality of life is greatly compromised in most patients with moderate or severe chronic GVHD that occurs in 40% of HCT recipients. Moreover, prolonged GVHD precludes the use of T cell immunotherapy to prevent or manage recurrence of leukemia following HCT. T cell depletion is the only current alternative to immunosuppressive drugs and, although effective for preventing GVHD, is complicated by slow immune recovery and high rates of opportunistic infection. The objective of the project is to develop an improved HCT strategy to prevent GVHD, provide for rapid reconstitution of pathogen-specific immunity, and facilitate future immunotherapeutic approaches to reduce relapse in the absence of immunosuppressive drugs. Preclinical studies in murine models by several groups, including by our co-investigator W. Shlomchik, have demonstrated that transplant of purified allogeneic memory T cells (TM) caused less GVHD than did na�ve (TN) or unfractionated T cells. Informed by these studies, we initiated a first-in-human clinical trial to evaluate whether selective depletion of TN from allogeneic PBSC grafts combined with tacrolimus monotherapy could abrogate GVHD and preserve immune reconstitution in recipients of matched related donor (MRD) HCT for acute leukemia. Our preliminary data demonstrates reproducible stem cell engraftment, mild gastrointestinal acute GVHD, a very low incidence of chronic GVHD, rapid reconstitution of pathogen-specific immunity, low levels of relapse and treatment-related mortality and high overall survival. Here, we seek to improve upon these exciting initial results of TN depletion in MRD recipients, and extend this approach to matched unrelated donor (MUD) HCT. The proposed clinical trial will be complemented by detailed correlative and mechanistic laboratory studies, including an in-depth analysis of immune competence and studies to evaluate potential differences in gastrointestinal immune infiltrates and intestinal stem cell damage in recipients of TN-depleted and T cell-replete HCT. The results of the proposed studies have the potential to reduce GVHD and the duration of immunosuppression, which would fundamentally change our approach to allogeneic MRD and MUD HCT, and to provide insight into the pathogenesis of acute GVHD. The specific aims are: 1. To determine whether depletion of TN from PBSC grafts followed by tacrolimus and a short course of methotrexate can reduce GVHD in MRD and MUD HCT recipients. 2. To evaluate reconstitution of pathogen-specific and regulatory T cells, T cell receptor diversity, and immune responses to new antigens delivered by vaccination in TN-depleted and T cell-replete HCT recipients. 3. To evaluate infiltrating T cells and intestinal stem cell damage in recipients of TN-depleted and T cell-replete HCT with GVHD.

描述（由申请人提供）：同种异体造血细胞移植 (HCT) 通常可以治愈许多其他致命的恶性和非恶性疾病。然而，单独使用药物免疫抑制的传统 T 细胞 HCT 常常会因移植物抗宿主病 (GVHD) 而变得复杂。 16% 的 HCT 接受者发生归因于 GVHD 的疾病，大多数患有中度或重度慢性 GVHD 的患者的生活质量受到严重影响，此外，40% 的 HCT 接受者会出现长期 GVHD，无法使用 T 细胞免疫疗法来预防或控制 HCT 后的白血病复发。T 细胞耗竭是目前免疫抑制药物的唯一替代方案，尽管可以有效预防 GVHD，但其过程很复杂。该项目的目标是开发一种改进的 HCT 策略来预防 GVHD，提供病原体特异性免疫的快速重建，并促进未来的免疫治疗方法可在缺乏免疫抑制药物的情况下减少复发。包括我们的共同研究员 W. Shlomchik 在内的多个研究小组在小鼠模型中进行的临床前研究表明，移植纯化的同种异体记忆 T 细胞 (TM) 引起的 GVHD 比以前少。根据这些研究，我们启动了一项首次人体临床试验，以评估 TN 是否会被选择性去除。同种异体 PBSC 移植物联合他克莫司单一疗法可以消除 GVHD 并保留匹配相关供体 (MRD) HCT 急性白血病受者的免疫重建。我们的初步数据表明，干细胞移植可重复，胃肠道急性 GVHD 发生率极低，在此，我们寻求改进病原体特异性免疫力、低复发率和治疗相关死亡率以及高总体生存率。 MRD 受体中 TN 消耗的这些令人兴奋的初步结果，并将这种方法扩展到匹配的无关供体 (MUD) HCT，拟议的临床试验将得到详细的相关和机制实验室研究的补充，包括对免疫能力和研究的深入分析。评估接受者胃肠道免疫浸润和肠道干细胞损伤的潜在差异 TN 耗尽和 T 细胞充足的 HCT 所提出的研究结果有可能减少 GVHD 和免疫抑制的持续时间，这将从根本上改变我们对同种异体 MRD 和 MUD HCT 的方法，并深入了解急性的发病机制。 GVHD 的具体目标是： 1. 确定从 PBSC 移植物中去除 TN，然后使用他克莫司和短疗程甲氨蝶呤是否可以降低 GVHD。 2. 评估 TN 耗尽和 T 细胞充足的 HCT 受者中病原体特异性和调节性 T 细胞的重建、T 细胞受体多样性以及对疫苗接种产生的新抗原的免疫反应。评估浸润性 T 细胞和肠干 TN 耗尽且 T 细胞充足的 HCT 伴 GVHD 受者的细胞损伤。