Exploiting NKG2C on adaptive NK cells for Immunotherapy

利用适应性 NK 细胞上的 NKG2C 进行免疫治疗

基本信息

批准号：
9920000
负责人：
Emily Chiu
金额：
$ 4.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920000
关键词：
Acute Myelocytic Leukemia Adaptor Signaling Protein Address Adult Affect Age Binding C-Type Lectins CD8-Positive T-Lymphocytes Cell Line Cells Cessation of life Clinical Clinical Trials Cytolysis Cytomegalovirus Development Disease Disease-Free Survival Equilibrium Exclusion Exhibits FCGR3B gene Family Family member Frequencies HLA Antigens Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hepatitis B e Antigens Human Immunotherapy In Vitro Individual Ink Interleukin-15 K-562 K562 Cells KLRD1 gene Knowledge Ligation Link Major Histocompatibility Complex Malignant - descriptor Measurable Mediating Membrane Memory NK Cell Activation Natural Killer Cells Patients Pattern Peptides Phenotype Physiological Play Population Production Regimen Relapse Role Signal Transduction Specificity Stem cell transplant Surface T-Lymphocyte Subsets TYROBP gene Technology Testing Therapeutic Transcriptional Regulation Transplantation Tumor Burden Tyrosine Viral arm base cancer therapy cancer type cell transformation chemoradiation chemotherapy conditioning curative treatments cytokine cytotoxicity dimer experimental study extracellular high risk immunological synapse improved in vivo induced pluripotent stem cell member mortality mouse model myeloid leukemia cell neoplasm immunotherapy neoplastic cell neutrophil new therapeutic target novel older patient peripheral blood prevent protein expression receptor relapse risk response seropositive trispecific killer engager tumor

项目摘要

Project Summary/Abstract Acute myeloid leukemia (AML) is a challenging disease to cure. The only known “cure” currently is hematopoietic stem cell transplantation (HSCT) which requires conditioning prior to transplantation. The population that AML affects does not tolerate myeloablative conditioning well so a reduced intensity conditioning is used instead. However, the relapse rate is unacceptably high in patients that receive reduced intensity conditioning. Immunotherapy is a promising new field for treatment of all cancer types and we aim to improve immunotherapy for AML patients. The benefits of targeting NK cells lie within its inherent tumor surveillance ability. Adaptive NK cells, which are expanded after cytomegalovirus (CMV) reactivation, are a subtype of NK cells that display enhanced killing and cytokine production. Adaptive NK cells are considered adaptive because of their memory-like phenotype, showing enhanced activation following re-exposure. Adaptive NK cells are also associated with lower relapse following HSCT. Adaptive NK cells are easily identified as CD57+NKG2C+. The function of NKG2C has not been thoroughly defined on adaptive NK cells. NKG2C binds to HLA-E, a non- classical major histocompatibility complex (MHC) class I molecule, with peptide specificity to activate NK cells. NKG2C+ cells also downregulate NKG2A, a family member of NKG2C that also binds to HLA-E with peptide specificity but inhibits NK cells. Our proposal aims to exploit NKG2C on adaptive NK cells for tumor immunotherapy. In Aim 1, we look at the role of NKG2C specifically on adaptive NK cells. We will use a cell line, K562, that lack MHC class I molecules resulting in potent NK cell activation due to lack of inhibition. We will manipulate these cells to express HLA-E (K562-E) and with these cells to determine whether there is a signaling function through NKG2C that is unique to adaptive NK cells or whether it is the decrease in NKG2A expression and subsequent reduction of inhibition in adaptive NK cells that leads to their enhanced function. We can use peripheral blood NK cells to study the function of NKG2C on adaptive NK cells, but the number of adaptive NK cells in humans is variable. In Aim 2, we will use induced pluripotent stem cell (iPSC) derived NK cells (iNK) with transduced NKG2C to kill tumor cells. We will specifically target tumor cells using a Trispecific Killer Engager that activates NKG2C on the iNK, linking them with tumor target while simultaneously stimulating NKG2C and IL15 receptor. Aim 2 creates a specific translational therapy that can be scaled for clinical trials. Overall, this project aims to exploit NKG2C as a functional receptor for immunotherapy.

项目概要/摘要急性髓系白血病（AML）是一种具有挑战性的疾病，目前唯一已知的“治愈方法”是。造血干细胞移植（HSCT）需要在移植前进行预处理。 AML 影响的人群不能很好地耐受清髓性训练，因此需要降低强度的训练然而，接受强度降低的患者的复发率高得令人无法接受。免疫疗法是治疗所有癌症类型的一个有前景的新领域，我们的目标是改进。针对 AML 患者的免疫疗法的好处在于其固有的肿瘤监测。适应性 NK 细胞在巨细胞病毒 (CMV) 重新激活后扩增，是 NK 的一种亚型。适应性 NK 细胞具有更强的杀伤能力和细胞因子生成能力，因此被认为具有适应性。它们的记忆样表型，在重新暴露后也显示出增强的激活。与 HSCT 后较低的复发率相关，适应性 NK 细胞很容易被识别为 CD57+NKG2C+。 NKG2C 在适应性 NK 细胞中的功能尚未完全明确。经典的主要组织相容性复合体 (MHC) I 类分子，具有激活 NK 细胞的肽特异性。 NKG2C+ 细胞还会下调 NKG2A，NKG2A 是 NKG2C 的家族成员，也通过肽与 HLA-E 结合特异性但抑制 NK 细胞我们的建议旨在利用 NKG2C 对肿瘤的适应性 NK 细胞。在目标 1 中，我们将特别研究 NKG2C 对适应性 NK 细胞的作用。 K562，缺乏 MHC I 类分子，由于缺乏抑制而导致 NK 细胞的有效激活。操纵这些细胞表达 HLA-E (K562-E) 并用这些细胞来确定是否存在信号传导是通过适应性 NK 细胞特有的 NKG2C 发挥作用，还是 NKG2A 表达减少以及随后减少适应性 NK 细胞的抑制，从而增强其功能。外周血NK细胞研究NKG2C对适应性NK细胞的功能，但适应性NK的数量在目标 2 中，我们将使用诱导多能干细胞 (iPSC) 衍生的 NK 细胞 (iNK)。转导 NKG2C 来杀死肿瘤细胞我们将使用三特异性杀伤剂接合器特异性靶向肿瘤细胞。激活 iNK 上的 NKG2C，将其与肿瘤靶标连接起来，同时刺激 NKG2C 和 IL15 受体。目标 2 创建了一种可扩展用于临床试验的特定转化疗法。该项目旨在利用 NKG2C 作为免疫治疗的功能性受体。