Optimizing NK Education and Alloreactivity after HLA-Haploidentical Allogeneic Hematopoietic Cell Transplantation

HLA-单倍体同种异体造血细胞移植后优化 NK 教育和同种异体反应性

• 批准号: 10229526
• 负责人: Brian Shaffer
• 金额: $ 14.84万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229526
• 关键词: Acute; Address; Algorithms; Alleles; Allogenic; Allografting; Award; Bone Marrow Transplantation; Cause of Death; Cell Surface Proteins; Cell surface; Cells; Clinical Trials; Cyclophosphamide; Cytomegalovirus; Disease; Disease-Free Survival; Donor person; Education; Effector Cell; Engraftment; Environment; Family member; Genetic Materials; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Graft-Versus-Tumor Induction; Grant; HLA Antigens; Hematologic Neoplasms; Histology; Immune; In Vitro; Incidence; Individual; Kinetics; Laboratories; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mentors; Methods; Modality; Myeloproliferative disease; NK Cell Activation; NK cell receptor NKB1; Natural Increases; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Outcome; Participant; Patients; Persons; Population; Process; Progression-Free Survivals; Prophylactic treatment; Reaction; Receptor Gene; Relapse; Research; Resolution; Retrospective cohort; Role; Sampling; Siblings; Source; Specimen; Stereotyping; Stratification; Stromal Cells; T-Lymphocyte; Testing; Transplant Recipients; Transplantation; Universities; Virus Diseases; Work; base; cancer cell; career; chronic graft versus host disease; cost effective; cytotoxicity; disorder prevention; effective therapy; ethnic minority population; fighting; graft vs host disease; hematopoietic cell transplantation; high risk; improved; improved outcome; innovation; inter-individual variation; killer immunoglobulin-like receptor; mortality; novel; post-transplant; prevent; primary endpoint; racial minority; receptor; secondary endpoint; uptake

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation is an effective therapy for patients with high risk hematologic malignancies. This is due to a well recognized graft versus tumor reaction mediated in part by donor natural killer (NK) cells. NK cell cytotoxicity against malignant cells is controlled by an array of cell surface proteins, including the killer Ig-like receptors (KIR), which interact with class 1 human leukocyte antigens (HLA) on target cells to calibrate NK cell effector function. KIR are genetically diverse: Significant inter-individual variation exists in terms of the number of KIR genes expressed and allelic polymorphism within individual KIR genes. This genetic variation determines KIR proteins with variegated capacity to activate or inhibit the NK cell when taken into consideration with the transplant recipient’s HLA. Therefore, genotyping of donor KIR/recipient HLA is a potential mechanism to define and select allogeneic donors that have more alloreactive NK cells, thereby preventing relapse in the transplant recipient. Allogeneic hematopoietic cell transplantation (allo HCT) was historically offered only to patients with high risk malignancies who had HLA matched sibling or unrelated donors. HLA-haploidentical donors are partially matched, familial donors that are available in >95% of patients, but were previously avoided as donors due to their resulting in a high incidence of graft versus host disease (GVHD) after transplantation. Recent advances in GVHD prevention using post-transplant cyclophosphamide have decreased the incidence of transplant related mortality to <10-20% after haploidentical donor allografts. Despite this, relapse occurs in 30-60% of haplotransplant recipients and is the most frequent cause of death in these patients. As haploidentical donors represent a broadly available and cost effective donor source, optimizing their efficacy is an important step in improving transplant outcomes. These results are particularly applicable to persons of ethnic and/or racial minorities, who are more frequently without a HLA matched donor option. The purpose of the proposed grant is to use KIR gene and allele typing to identify haploidentical donors with greater predicted NK alloreactivity against recipient malignant cells. Using a set of 450 donor/recipient pairs, this proposal will test the hypothesis that greater donor NK alloreactivity will result in decreased relapse and improved relapse-free survival in haplotransplant recipients. In a second aim, this proposal will address the hypothesis that HLA may be passed from recipient stromal cells to donor NK cells and will examine the resulting effects of HLA exchange on donor NK cell activation state after transplantation.

项目概要 异基因造血细胞移植是治疗高危血液病患者的有效方法 恶性肿瘤。这是由于公认的移植物抗肿瘤反应，部分是由供体天然介导的 杀伤 (NK) 细胞。 NK 细胞针对恶性细胞的细胞毒性是由一系列细胞表面蛋白控制的， 包括杀伤性 Ig 样受体 (KIR)，它与目标上的 1 类人类白细胞抗原 (HLA) 相互作用 细胞来校准 NK 细胞效应功能。 KIR 具有遗传多样性：显着的个体间差异 存在于表达的 KIR 基因数量和单个 KIR 基因内的等位基因多态性方面。 这种遗传变异决定了 KIR 蛋白在以下情况下具有激活或抑制 NK 细胞的多种能力： 考虑移植受者的 HLA。因此，供体 KIR/受体 HLA 的基因分型 是一种潜在机制，用于定义和选择具有更多同种异体反应性 NK 细胞的同种异体供体，从而 预防移植受者的复发。 异基因造血细胞移植（allo HCT）历来只提供给高危患者 患有 HLA 匹配的兄弟姐妹或无关捐赠者的恶性肿瘤。 HLA-半相合供体是部分 匹配的家族捐献者可用于 >95% 的患者，但之前由于以下原因而避免作为捐献者 它们导致移植后移植物抗宿主病（GVHD）的高发生率。最新进展 使用移植后环磷酰胺预防 GVHD 降低了移植发生率 半相合供体同种异体移植后相关死亡率<10-20%。尽管如此，仍有 30-60% 的人复发 单倍体移植受者，是这些患者最常见的死亡原因。作为单倍体捐献者 代表了广泛可用且具有成本效益的捐助来源，优化其功效是重要的一步 改善移植结果。这些结果特别适用于民族和/或种族的人 少数群体，他们更经常没有 HLA 匹配的捐赠者选择。 拟议拨款的目的是使用 KIR 基因和等位基因分型来识别具有 预测 NK 对受体恶性细胞的同种反应性更高。使用一组 450 个捐赠者/接受者对， 该提案将检验以下假设：较高的供体 NK 同种异体反应性将导致复发率降低，并且 提高单倍体移植受者的无复发生存率。第二个目标是，该提案将解决 假设 HLA 可能从受体基质细胞传递到供体 NK 细胞，并将检查 HLA 交换对移植后供体 NK 细胞活化状态的影响。

项目成果

Improved GRFS after posttransplant cyclophosphamide-based vs ATG-based HLA-mismatched unrelated donor transplant.

• DOI: 10.1182/bloodadvances.2022007596
• 发表时间: 2022-08-09
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Jimenez, Antonio Jimenez;Komanduri, Krishna;Brown, Samantha;Wang, Trent;Pereira, Denise;Goodman, Mark;Beitinjaneh, Amer;Lekakis, Lazaros;Chinapen, Stephanie;Devlin, Sean;Ponce, Doris;Sauter, Craig;Perales, Miguel-Angel;Shaffer, Brian C.
• 通讯作者: Shaffer, Brian C.