UCB-DERIVED CD19-SPECIFIC T CELLS FOR UNIVERSAL TREATMENT OF B-CELL MALIGNANCY

UCB 衍生的 CD19 特异性 T 细胞用于 B 细胞恶性肿瘤的通用治疗

• 批准号: 7240937
• 负责人: Laurence J.N. Cooper
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-25 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7240937
• 关键词: Acute Lymphocytic Leukemia; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Allogenic; Antigen Receptors; Antigens; Apoptotic; Autologous; B lymphoid malignancy; B-Lymphocytes; CD19 Antigens; CD19 gene; CD28 gene; CD3 Antigens; CD8B1 gene; Cell Lineage; Cell Separation; Cell surface; Cells; Clinical; Clinical Data; Clinical Trials; Cytolysis; Data; Disease; Dose; Effector Cell; Environment; Epitopes; Follicular Lymphoma; Generations; Genes; Genetic; Graft-Versus-Tumor Induction; Grant; Hematopoietic; Hematopoietic stem cells; Herpesvirus 1; Human; Image; In Vitro; Infusion procedures; Language; Lymphoma; Malignant Neoplasms; Measures; Modification; Mus; Non-Hodgkin' s Lymphoma; Numbers; Patients; Phase; Phase I Clinical Trials; Plasmids; Population; Positron-Emission Tomography; Procedures; Production; Quality Control; Radiation therapy; Radio; Recurrence; Relapse; Safety; Signal Transduction; Source; Standards of Weights and Measures; Stem cell transplant; T-Cell Activation; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Thymidine Kinase; Toxic effect; Transcriptional Activation; Transgenes; Translating; Tumor Antigens; Umbilical Cord Blood; United States Food and Drug Administration; University of Texas M D Anderson Cancer Center; Up-Regulation; cell bank; cytokine; design; desire; gene therapy; graft vs host disease; immunogenic; improved; in vivo; killings; leukemia; leukemia/lymphoma; manufacturing process; neoplastic cell; pre-clinical; promoter; receptor binding; tumor

DESCRIPTION (provided by applicant): Currently, there are no effective treatments for disease recurrence following allogeneic hematopoietic stem- cell transplant (HSCT). T-cell therapy can target malignancies using mechanisms independent of chemo- radiotherapy, with non-overlapping and generally mild toxicities. Thus, we are investigating adoptive immunotherapy as a strategy to augment the graft-versus-tumor (GVT) effect after allogeneic HSCT. However, this approach has been limited by problems delineating immunogenic epitopes for a large number of HLA alleles, T-cell tolerance to leukemia-associated antigens, and the difficulty of manufacturing patient- specific T cells in a timely manner. As an alternative strategy, we propose to use T cells genetically modified to express a chimeric antigen receptor (CAR) specific a desired tumor antigen independent of MHC. To target B-cell malignancies, we have designed a CAR which re-directs the antigen-specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19. CD19 is expressed on the majority of B-lineage leukemia or lymphoma cells, but is absent on hematopoietic stem cells and non-hematopoietic cells. Genetically modified CD19-specific T cells are activated via chimeric CD3-^ upon CAR binding CD19, resulting in antigen-dependent cytokine production, killing and proliferation. These preclinical data were used to open a Phase I clinical trial (BB-IND 11411) infusing autologous CD19-specific T cells (expressing the first-generation CAR) in patients with relapsed follicular lymphoma. In this grant, we propose a new clinical trial to infuse pre-prepared CD19-specific T cells derived from umbilical cord blood (UCB) in patients with relapsed B-lineage leukemia/lymphoma after allogeneic HSCT. Significantly, this trial will be (i) the "first-in- human" infusion of CD19-specific T cells after allogeneic HSCT, (ii) the first to infuse T cells expressing a second-generation CAR capable of providing a fully-competent T-cell activation signal (through chimeric CD3-¿; and CD28), and (iii) the first to image distribution of genetically modified T cells and their activation status in vivo by positron emission tomography (PET), an example of radio-gene-therapy. We hypothesize that the a priori generation of banks of a homogenous population of UCB-derived HLA-unmatched CD19- specific T-cell clones will permit infusion of T cells in a safe and timely manner in a patient population with little chance of survival. T-cell isolation, genetic modification, and expansion will follow Standard Operating Procedures at MDACC, and T-cell doses will be manufactured in our Good Manufacturing Process (GMP) facility in accordance with quality control/assurance standards mandated by the FDA for a master cell bank. Lav language: T cells will be developed which can destroy B-lineage disease.

描述（由适用提供）：目前，在同种异性造血干细胞移植（HSCT）后，没有有效的疾病复发治疗方法。 T细胞疗法可以使用与化学放射疗法无关的机制靶向恶性肿瘤，具有非重叠和通常轻度毒性的机制。这是，我们正在研究适应性免疫疗法，作为同种异体HSCT后增强移植物肿瘤（GVT）效应的一种策略。然而，这种方法受到有关大量HLA等位基因的免疫原性表位的问题的限制，对白血病相关抗原的T细胞耐受性以及及时制造患者特异性T细胞的困难。作为另一种策略，我们建议使用基因修饰的T细胞表达嵌合抗原受体（CAR）特异性的一种所需的肿瘤抗原，而与MHC无关。为了靶向B细胞恶性肿瘤，我们设计了一种汽车，该汽车将T细胞的抗原特异性重新引向B细胞谱系限制的细胞表面分子CD19。 CD19在大多数B-Linege白血病或淋巴瘤细胞上表达，但在造血干细胞和非造血细胞上不存在。在CAR结合CD19时，通过嵌合CD3-^激活了基因修饰的CD19特异性T细胞，从而导致抗原依赖性的细胞因子产生，杀伤和增殖。这些临床前数据用于打开I期临床试验（BB-IND 11411），中注入自体CD19特异性T细胞（表达第一代汽车），患有复发性卵泡淋巴瘤的患者。在这笔赠款中，我们提出了一项新的临床试验，以对同种异体HSCT后复发性B-Linege白血病/淋巴瘤的患者注入源自脐带血（UCB）的预先准备的CD19特异性T细胞。 Significantly, this trial will be (i) the "first-in-human" infusion of CD19-specific T cells after allogeneic HSCT, (ii) the first to infuse T cells expressing a second-generation CAR capable of providing a fully-competent T-cell activation signal (through chimeric CD3-¿ ; and CD28), and (iii) the first to image distribution of generically modified T cells and their activation status in vivo by positron排放断层扫描（PET），无线电治疗的一个例子。我们假设，先验生成UCB衍生的HLA无匹配的CD19-特异性T细胞克隆的同质群体将允许在患者人群中以安全而及时的方式注入T细胞，而生存的可能性很小。 T细胞隔离，遗传修饰和扩展将遵循MDACC的标准操作程序，根据FDA为主电池银行规定的质量控制/保证标准，将在我们的良好制造工艺（GMP）设施中制造T细胞剂量。 LAV语言：将开发出可能破坏B-Linege疾病的T细胞。