CD19-Specific CB T-cell Therapy for Patients with B-cell Malignancies

针对 B 细胞恶性肿瘤患者的 CD19 特异性 CB T 细胞疗法

基本信息

批准号：
8555383
负责人：
Gianpietro Dotti
金额：
$ 41.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555383
关键词：
Acute Lymphocytic Leukemia Address Adenoviruses Adoptive Immunotherapy Adoptive Transfer Adult Allogenic Antigen Receptors Antigens Apoptotic Applications Grants Asses B lymphoid malignancy B-Lymphocytes Biological Assay CD19 Antigens CD19 gene CD28 gene CD3 Antigens CD34 gene Cell Lineage Cell surface Cells Childhood Collaborations Correlative Study Cytolysis Cytomegalovirus Cytotoxic T-Lymphocytes Development Disease-Free Survival Evolution Gene Transfer Genes Guanine Nucleotide Dissociation Inhibitors Herpesvirus 1 Human Human Herpesvirus 4 Image Imaging technology Immune Immune response Immunity Immunodeficient Mouse Immunologics Incidence Infection Infection prevention Infusion procedures Interleukin-2 Leukemic Cell Lymphoid Cell Macaca Malignant Neoplasms Measurement Measures Mediating Medical center Memory Modeling Monitor Monkeys Morbidity - disease rate Patients Phase I Clinical Trials Positron-Emission Tomography Preparation Procedures Relapse Reporter Genes Research Personnel Risk Safety Specificity T cell therapy T-Lymphocyte Testing Texas Therapeutic Thymidine Kinase Transgenes Transplant Recipients Transplantation Treatment Failure Umbilical Cord Blood Transplantation Variant Viral Viral Antigens Virus Virus Diseases X-Ray Computed Tomography base cellular engineering cellular imaging design graft vs host disease humanized SCID mouse improved in vivo leukemia leukemia virus longitudinal positron emission tomography mortality mouse model nonhuman primate peripheral blood prevent reconstitution response success trafficking tumor viral leukemia whole body imaging

项目摘要

Project 3 addresses the problems of (i) opportunistic viral infection and (ii) relapse of B-lineage malignancies after umbilical cord blood transplantation (UCBT). We hypothesize that the incidence of viral infection and leukemia relapse following allogeneic UCBT can be reduced by adoptively transferred donor-derived multi virus-specific cytotoxic T lymphocytes (CTL), genetically modified (transduced) to be specific for the CD19 molecule expressed by leukemic cells. To consolidate UCBT we have designed a chimeric antigen receptor (CAR) to redirect antigen specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19 The virus-specific CTLs from Project 2 will be transduced to express this CAR, resulting in MHC-independent and CAR-dependent activation through chimeric CD28 and CD3-zeta to lyse lymphoid cells, upregulate IL-2, and anti-apoptotic genes in response to CD19. The studies proposed in Specific Aim #1 will evaluate whether UCB-derived multivirus-specific CTLs can be rendered specific for GDI 9 and whether HSV-1 thymidine kinase transgene can be expressed for imaging by positron emission tomography (PET) in immunodeficient mice. Adoptive immunotherapy using non-invasive bioluminescent imaging (BLI) and micro PET will longitudinally asses the persistence of the infused cells, and the anti-tumor effect. Specific Aim #2 will evaluate the feasibility, safety, and persistence of infusing multivirus-specific CTLs modified to express CAR CD19-specific after UCBT. The correlative studies will delineate the (i) magnitude and duration of persistence, (ii) trafficking, and (iii) anti-viral and anti-leukemic effects of adoptively transferred CTLs. In preparation for human PET T-cell imaging, in Specific Aim #3, we will develop a nonhuman primate model Monkey-derived T cells will be genetically modified with CARs and TK, and infused. Longitudinal PET imaging using [18FJFEAU, metabolized by thymidine kinase (TK) will be used to evaluate the distribution of these adoptively transferred macaque T cells. In aggregate, the results of the studies will facilitate the evolution of targeting post-UCBT MRD with viral- and CD19-specific CTLs for enhanced disease-free survival of patients with B cell malignancies.

项目3解决了（i）机会性病毒感染和（ii）脐带血液移植后B局部恶性肿瘤的复发（UCBT）。我们假设同种异体UCBT后，病毒感染和白血病复发的发生率可以通过通过过继转移的供体衍生的多个病毒特异性细胞毒性T淋巴细胞（CTL），遗传改性（转引发）来降低，以特定于CD19分子通过LEUKECTER由Leukeption表达的细胞。为了巩固UCBT，我们已经设计了一种嵌合抗原受体（CAR），以将T细胞的抗原特异性重定向到B细胞谱系限制的细胞表面分子CD19项目2的病毒特异性CTL将被转导该病毒特异性的CTL，以表达该汽车，从而表达MHC依赖性和CARA依赖性CD28和CD28的CD28，并导致CD28的CD28。响应CD19的上调IL-2和抗凋亡基因。特定目标＃1中提出的研究将评估是否可以针对GDI 9进行特异性UCB衍生的多病毒特异性CTL，以及是否可以通过对免疫缺陷小鼠中的potitron发射层析成像（PET）来表达HSV-1-甲状腺素激酶转基因。使用非侵入性生物发光成像（BLI）和微PET的收养免疫疗法将纵向纵向评估注入的细胞的持久性和抗肿瘤效应。特定的目标＃2将评估在UCBT之后经过修改以表达CAR CD19特异性的多病毒特异性CTL的可行性，安全性和持久性。相关研究将描述（i）持久性，（ii）贩运的幅度和持续时间，以及（iii）采用转移的CTL的抗病毒和抗白血病作用。为了准备人类的宠物T细胞成像，在特定的目标＃3中，我们将开发一种非人类灵长类动物模型猴子衍生的T细胞，将用汽车和TK进行基因修饰，并注入。使用[18fjfeau，由胸苷激酶代谢（TK）代谢的纵向PET成像将用于评估这些经过转移的猕猴T细胞的分布。总体而言，研究结果将有助于用病毒和CD19特异性CTL靶向UCBT MRD的演变，以增强B细胞恶性肿瘤患者的无疾病生存。