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 (i) 机会性病毒感染和 (ii) 脐带血移植 (UCBT) 后 B 系恶性肿瘤复发的问题。我们假设，通过过继转移供体来源的多病毒特异性细胞毒性 T 淋巴细胞 (CTL)，对白血病细胞表达的 CD19 分子进行基因改造（转导），可以降低同种异体 UCBT 后病毒感染和白血病复发的发生率。为了巩固 UCBT，我们设计了一种嵌合抗原受体 (CAR)，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 中的病毒特异性 CTL 将被转导以表达该 CAR，从而产生通过嵌合 CD28 和 CD3-zeta 进行不依赖 MHC 和 CAR 依赖的激活，裂解淋巴细胞、上调 IL-2 和抗凋亡基因，以响应CD19。具体目标#1中提出的研究将评估UCB衍生的多病毒特异性CTL是否可以对GDI 9具有特异性，以及HSV-1胸苷激酶转基因是否可以在免疫缺陷小鼠中通过正电子发射断层扫描（PET）进行成像。使用非侵入性生物发光成像 (BLI) 和微型 PET 的过继免疫疗法将纵向评估输注细胞的持久性和抗肿瘤效果。具体目标#2 将评估 UCBT 后输注经过修饰以表达 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）持续性的程度和持续时间，（ii）贩运，以及（iii）过继转移的 CTL 的抗病毒和抗白血病作用。为了准备人类 PET T 细胞成像，在具体目标 #3 中，我们将开发一种非人类灵长类动物模型，猴源 T 细胞将用 CAR 和 TK 进行基因改造，并进行输注。使用由胸苷激酶 (TK) 代谢的 [18FJFEAU] 进行的纵向 PET 成像将用于评估这些过继转移的猕猴 T 细胞的分布。总的来说，这些研究结果将促进用病毒和 CD19 特异性 CTL 靶向 UCBT 后 MRD 的发展，以提高 B 细胞恶性肿瘤患者的无病生存率。