Ex Vivo Alloanergization to Improve Immunity After Haploidentical Transplant

描述（申请人提供）：同种异体造血干细胞移植（HSCT）是治疗许多恶性疾病的有效方法。然而，许多患者缺乏匹配的hla供体，特别是那些少数民族或混合种族或民族。几乎所有患者都有单倍体相同的家庭供体，这将大大增加HSCT作为一种治疗方式的可用性。然而，单倍体造血干细胞移植导致急性移植物抗宿主病（aGvHD）的频率和严重程度增加，由同种异体反应性供体T细胞介导。尽管单倍体供体移植物的非选择性T细胞耗损有效地预防了严重的aGvHD，但它延迟了免疫重建，增加了感染并发症和复发率，限制了单倍体移植的成功。因此，已经开发了几种策略来选择性地去除或灭活供体T细胞池中的同种异体反应性T细胞，以产生能够赋予有益免疫重建的细胞产物，而不会产生严重的aGvHD。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（“同种异体能化”），诱导供体T细胞中的同种异体抗原特异性低反应性。这一策略在两项试点研究中成功应用，在这些研究中，将大剂量的单倍体同种异体失能供体T细胞大量注入供体骨髓（BM），导致aGvHD的严重程度低于历史上未处理的单倍体骨髓移植受体。没有死亡可归因于巨细胞病毒或其他病毒感染，这表明供体T细胞保留了功能性病原体特异性免疫，12例可评估的患者中只有1例发展为慢性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，单倍体同种异体变性脑转移术后可出现良好的长期功能预后，但仍有两个重要问题未得到解答。首先，异体失能T细胞的最佳剂量是多少，其次，输入这些细胞是否能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。将采用适应性剂量递增设计和更耐受的调理方案。从cd34选择的外周血中给予大剂量的单倍体相同供体干细胞，然后延迟输注经改进方法能化的单倍体相同供体T细胞。在Specific Aim 1中，我们将确定多机构进行这种新型细胞处理和I期临床试验的可行性。特异性目标2侧重于研究患者样本中病原体和肿瘤相关抗原特异性T细胞免疫的测量。特异性Aim 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，通过这种机制，失能策略似乎有助于体内同种异体抗原的低反应性。从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造血干细胞移植发病率和死亡率的潜力。公共卫生相关性：许多有可能通过造血干细胞移植治愈的疾病的患者找不到匹配的供体，尽管大多数患者有“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，要么是供体免疫细胞攻击患者（所谓的移植物抗宿主病（GvHD）），要么是供体免疫细胞被移除后免疫功能低下。我们已经证明，错配的家族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，但我们不知道耐受免疫细胞的最佳数量，也不知道它们可能产生什么免疫益处。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

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