Ex Vivo Alloanergization to Improve Immunity After Haploidentical Transplant

描述（由申请人提供）：异基因造血干细胞移植（HSCT）可治愈许多恶性疾病患者。然而，许多患者缺乏HLA匹配的供体，特别是那些少数民族或混合种族或民族的患者。几乎所有患者都有可用的单倍体相合家庭供体，使用这些供体将显著增加HSCT作为治疗方式的可用性。然而，单倍体相合HSCT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）的频率和严重程度增加。尽管单倍体相合供体移植物的非选择性T细胞耗竭有效地预防了严重的aGvHD，但它延迟了免疫重建并增加了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供体T细胞库中的同种异体反应性T细胞，以产生能够赋予有益的免疫重建而没有严重的aGvHD的细胞产物。一种这样的策略是通过受体同种异体抗原呈递与同时的共刺激阻断（"同种异体无反应化"）在供体T细胞中诱导同种异体抗原特异性低反应性。该策略成功地应用于2项试点研究，其中将大剂量的单倍体相合的同种异体供体T细胞与供体骨髓（BM）一起大量输注，导致aGvHD的严重程度低于历史上在未操作的单倍体相合BMT的受体中所见。没有死亡归因于CMV或其他病毒感染，表明供体T细胞保留了功能性病原体特异性免疫，12例可评估患者中仅1例发生慢性GvHD。24例高风险患者中有8例无病生存，表现评分正常（中位随访8年）。尽管这些研究表明，在单倍体相合的异体无能量化BMT后可以发生有利的长期功能结果，但两个重要的问题仍然没有答案。首先，同种异体T细胞的最佳剂量是多少，其次，通过输注这种细胞是否改善了抗原特异性免疫重建？我们提出了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预处理方案。将给予更大剂量的来自CD 34选择的外周血的单倍体相合供体干细胞，然后延迟输注用改进的方法进行同种异体活化的单倍体相合供体T细胞。在具体目标1中，我们将确定多机构进行新型细胞处理和I期临床试验的可行性。特定目标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将量化和表征供体来源的CD4 + T调节细胞在接受治疗的患者中的功能，从而进一步研究一种新的机制，通过该机制，无能量化策略似乎有助于体内同种异体抗原低反应性。从拟议的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。公共卫生相关性：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，尽管大多数患者具有"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并发症，或者是供体免疫细胞攻击患者（所谓的移植物抗宿主病（GvHD）），或者是如果供体免疫细胞被移除，则会导致免疫功能低下。我们已经表明，错配的家庭供体免疫细胞对移植受体"耐受"可能会减少错配移植后的GvHD，但我们不知道给予耐受的免疫细胞的最佳数量或它们可能产生的免疫益处。在这里，我们将进行一项临床试验，以确定耐受供体免疫细胞的数量 在不促进GVHD的情况下，改善不匹配的HSCT后的免疫功能是必要的，并进行实验室实验以表征实现这些目标的机制

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