Ex Vivo Alloanergization to Improve Immunity After Haploidentical Transplant

离体同种异能提高单倍体移植后的免疫力

• 批准号: 7772239
• 负责人: EVA C GUINAN
• 金额: $ 37.44万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772239
• 关键词: Acute Graft Versus Host Disease; Address; Adult; Alloantigen; Allogenic; Antigens; Bone Marrow; Bone Marrow Transplantation; Cell Therapy; Cell model; Cell physiology; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Cytomegalovirus; Data; Development; Disease; Dose; Engraftment; Ensure; Ethnic Origin; Evaluable Disease; Family; Frequencies; Future; Goals; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunity; In Vitro; Infusion procedures; Laboratories; Malignant - descriptor; Measurement; Measures; Mediating; Methods; Minority; Modality; Morbidity - disease rate; Multicenter Studies; Mus; Outcome; Patients; Performance; Phase I Clinical Trials; Pilot Projects; Population; Population Heterogeneity; Procedures; Process; Race; Regimen; Regulatory T-Lymphocyte; Relapse; Role; Safety; Sampling; Sampling Studies; Severities; Stem cells; T-Cell Depletion; T-Lymphocyte; Techniques; Transplant Recipients; Transplantation; Tumor Antigens; Umbilical Cord Blood; Virus Diseases; blood registry; chronic graft versus host disease; clinically significant; conditioning; design; follow-up; functional outcomes; graft vs host disease; high risk; immune function; improved; in vivo; mortality; novel; novel strategies; pathogen; peripheral blood; phase 1 study; prevent; public health relevance; reconstitution; research study; success

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with malignant diseases. However, many patients lack HLA-matched donors, particularly those of minority or mixed race or ethnicity. Almost all patients have available haploidentical family donors, the use of which would significantly increase the availability of HSCT as a treatment modality. However haploidentical HSCT results in an increased frequency and severity of acute graft versus host disease (aGvHD), mediated by alloreactive donor T cells. Although non-selective T cell depletion of haploidentical donor grafts effectively prevents severe aGvHD, it delays immune reconstitution and increases both infectious complications and relapse rates limiting the success of haploidentical HSCT. Several strategies have therefore been developed to selectively remove or inactivate alloreactive T cells within the donor T cell pool to create a cellular product capable of conferring beneficial immune reconstitution without severe aGvHD. One such strategy is induction of alloantigen-specific hyporesponsiveness in donor T cells by recipient alloantigen presentation with concurrent co-stimulatory blockade ("alloanergization"). This strategy was successfully employed in 2 pilot studies where large doses of haploidentical alloanergized donor T cells were infused en mass with donor bone marrow (BM), resulting in less severe aGvHD than seen historically in recipients of unmanipulated haploidentical BMT. No deaths were attributable to CMV or other viral infections, suggesting donor T cells retained functional pathogen-specific immunity, and only 1 of 12 evaluable patients developed chronic GvHD. Eight of 24 high risk patients survive disease-free with normal performance scores (median follow-up 8 years). Although, these studies demonstrate that favorable long-term functional outcome can occur after haploidentical alloanergized BMT, two important questions remained unanswered. Firstly, what is the optimal dose of alloanergized T cells, and secondly, is antigen-specific immune reconstitution improved by infusing such cells? We propose a new study to answer these questions. An adaptive, dose escalation design and more tolerable conditioning regimens will be used. Larger doses of haploidentical donor stem cells from CD34-selected peripheral blood will be given followed by delayed infusion of haploidentical donor T cells alloanergized with an improved method. In Specific Aim 1, we will determine the feasibility of multi-institutional conduct of the novel cell-processing and Phase I clinical trial. Specific Aim 2 focuses on measurement of pathogen- and tumor-associated antigen-specific T cell immunity in samples from study patients. Specific Aim 3 will quantify and characterize the function of donor-derived CD4+ T regulatory cells in patients so treated, thus further examining a novel mechanism by which anergization strategies appear to contribute to in vivo alloantigen hyporesponsiveness. The data derived from the proposed experiments will provide the necessary clinical and scientific information to design further pivotal studies that will determine the potential of this novel approach to ameliorate HSCT morbidity and mortality. PUBLIC HEALTH RELEVANCE: Many patients with diseases potentially curable by hematopoietic stem cell transplantation cannot find matched donors and although most have "mismatched" family donors, use of mismatched family donors often results in transplants complicated either by the donor immune cells attacking the patient (so-called Graft versus Host Disease (GvHD)) or by poor immune function if the donor immune cells are removed. We have shown that mismatched family donor immune cells "tolerized" to the transplant recipient may reduce GvHD after mismatched transplantation, but we do not know the best number of tolerized immune cells to administer or what immune benefits they may produce. Here, we will conduct a clinical trial to determine the number of tolerized donor immune cells necessary to improve immune function after mismatched HSCT without contributing to GVHD, and perform laboratory experiments to characterize the mechanisms by which these goals are achieved

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）对于许多恶性疾病患者都是治愈性的。但是，许多患者缺乏HLA匹配的捐助者，尤其是少数族裔或混合种族或种族的捐助者。几乎所有患者都有可用的单倍家庭捐助者，其使用将大大提高HSCT作为治疗方式。但是，单倍性HSCT导致急性移植物与宿主疾病（AGVHD）的频率和严重程度增加，这是由同种反应性供体T细胞介导的。尽管单倍性供体移植物的非选择性T细胞耗竭有效地防止了严重的AGVHD，但它会延迟免疫重建，并增加感染性并发症和复发率，从而限制了单倍性HSCT的成功。因此，已经制定了几种策略，以选择性地去除或灭活供体T细胞库中的同种反应性T细胞，以创建能够在没有严重AGVHD的情况下赋予有益的免疫重建的细胞产品。一种这样的策略是通过同剂呈现同时的共刺激性阻滞（“ alloananergization”）的受体表现，诱导供体T细胞中同种抗原特异性的低反应性。该策略成功地用于2项试验研究中，其中大剂量的单倍性同异氧供体T细胞与供体骨髓（BM）注入质量，导致AGVHD的严重程度低，而不是历史上未经操纵的单倍型BMT的接受者。没有死亡归因于CMV或其他病毒感染，这表明供体T细胞保留了功能性病原体特异性免疫，而12名可评估患者中只有1例出现了慢性GVHD。 24名高风险患者中有八名能够以正常的表现得分（中位随访8年）幸存下来。尽管这些研究表明，在单倍性同异化BMT后可能会发生有利的长期功能结果，但两个重要的问题仍未得到解答。首先，同烷耐受的T细胞的最佳剂量是什么？我们提出了一项新的研究来回答这些问题。将使用一种自适应，剂量升级设计和更耐受的调理方案。来自CD34选择的外周血的较大剂量的单倍性供体干细胞，然后通过改进的方法延迟输注单倍体供体T细胞。在特定目标1中，我们将确定新型细胞处理和I期临床试验的多机构行为的可行性。具体目标2的重点是研究患者的样品中病原体和肿瘤相关的抗原特异性T细胞免疫。特定的目标3将量化和表征如此治疗的患者中供体衍生的CD4+ T调节细胞的功能，从而进一步研究一种新型机制，通过该机制，纳入术策略似乎有助于体内同种抗菌剂的低温。从提出的实验中得出的数据将提供必要的临床和科学信息，以设计进一步的关键研究，以确定这种新颖的方法可以改善HSCT发病率和死亡率。公共卫生相关性：许多可能通过造血干细胞移植可治愈的疾病患者找不到匹配的供体，尽管大多数人具有“不匹配”的家庭捐助者，但使用不匹配的家庭供体通常会导致移植物与供体免疫细胞复杂的移植物相比，由患者攻击患者（所谓的嫁接与宿主疾病与GVHD的疾病）或不良免疫功能不适合免疫功能。我们已经表明，对移植受者的“耐受性耐受性”的家庭供体免疫细胞可能会减少不匹配移植后的GVHD，但我们不知道最佳的耐受性免疫细胞以给药或可能产生的免疫益处。在这里，我们将进行临床试验以确定耐受供体免疫细胞的数量 在不匹配HSCT的情况下不匹配GVHD并进行实验室实验以表征实现这些目标的机制，需要提高不匹配的HSCT后提高免疫功能