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

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：同种异体造血干细胞移植（HSCT）可以治愈许多患有恶性疾病的患者。然而，许多患者缺乏 HLA 匹配的捐献者，特别是少数族裔或混血儿或族裔的捐献者。几乎所有患者都有可用的半相合家庭供体，其使用将显着增加 HSCT 作为治疗方式的可用性。然而，半相合 HSCT 会导致由同种异体反应性供体 T 细胞介导的急性移植物抗宿主病 (aGvHD) 的发生频率和严重程度增加。虽然单倍体相合供体移植物的非选择性 T 细胞耗竭可有效预防严重的 aGvHD，但它会延迟免疫重建并增加感染并发症和复发率，限制了单倍体相合 HSCT 的成功。因此，已经开发了几种策略来选择性地去除或灭活供体 T 细胞库中的同种异体反应性 T 细胞，以创建能够赋予有益的免疫重建而无需严重的 aGvHD 的细胞产品。其中一种策略是通过受体同种异体抗原呈递并同时进行共刺激阻断（“同种异体赋能”）来诱导供体 T 细胞中同种异体抗原特异性低反应性。该策略已成功应用于两项试点研究，其中将大剂量的半相合同种异源供体 T 细胞与供体骨髓 (BM) 一起注入，与历史上未操作的半相合 BMT 受者相比，导致的 aGvHD 严重程度较低。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，并且 12 名可评估患者中只有 1 名出现慢性 GvHD。 24 名高危患者中有 8 名无病生存，体能评分正常（中位随访 8 年）。尽管这些研究表明半相合同种异能 BMT 后可以出现良好的长期功能结果，但两个重要问题仍未得到解答。首先，同种异体T细胞的最佳剂量是多少，其次，输注此类细胞是否可以改善抗原特异性免疫重建？我们提出一项新的研究来回答这些问题。将使用适应性剂量递增设计和更耐受的调理方案。将给予来自CD34选择的外周血的较大剂量的单倍体供体干细胞，然后延迟输注用改进的方法同种异源的单倍体供体T细胞。在具体目标 1 中，我们将确定多机构开展新型细胞加工和 I 期临床试验的可行性。具体目标 2 侧重于测量研究患者样本中的病原体和肿瘤相关抗原特异性 T 细胞免疫。具体目标 3 将量化和表征接受如此治疗的患者中供体来源的 CD4+ T 调节细胞的功能，从而进一步研究一种新的机制，通过该机制，失电策略似乎会导致体内同种异体抗原反应低下。从拟议实验中获得的数据将为设计进一步的关键研究提供必要的临床和科学信息，这些研究将确定这种新方法改善 HSCT 发病率和死亡率的潜力。公共健康相关性：许多患有可通过造血干细胞移植治愈的疾病的患者无法找到匹配的供体，尽管大多数患者都有“不匹配”的家庭供体，但使用不匹配的家庭供体通常会导致移植复杂化，因为供体免疫细胞会攻击患者（因此-称为移植物抗宿主病（GvHD））或由于供体免疫细胞被移除而导致免疫功能不良。我们已经证明，对移植受者“耐受”的不匹配的家族供体免疫细胞可能会减少不匹配移植后的 GvHD，但我们不知道要施用的耐受免疫细胞的最佳数量或它们可能产生什么免疫益处。在这里，我们将进行临床试验以确定耐受的供体免疫细胞的数量有必要在不匹配的 HSCT 后改善免疫功能而不导致 GVHD，并进行实验室实验来表征实现这些目标的机制