Adoptive immunotherapy after umbilical cord blood transplant

脐带血移植后的过继免疫治疗

基本信息

批准号：
7916047
负责人：
Laurence J.N. Cooper
金额：
$ 56.82万
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：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916047
关键词：
Ablation Acute Lymphocytic Leukemia Address Adoptive Immunotherapy Adoptive Transfer Advanced Development Affinity Aldesleukin Allogenic Anatomic Sites Antigen Receptors Antigens B-Lymphocytes Bone Marrow CD19 Antigens CD19 gene CD28 gene CD3 Antigens Cell Line Cell Lineage Cell Separation Cell surface Cells Chimeric Proteins Clinical Clinical Trials Complementary DNA Correlative Study Cytolysis Cytotoxic T-Lymphocytes Data Disease-Free Survival Dose Effector Cell Engineering Engraftment Evolution Extracellular Domain Ganciclovir Generations Genetic Glossary Guidelines Hematopoietic Hematopoietic Stem Cell Transplantation Human Immunoglobulins Immunotherapy Incidence Infusion procedures Laboratories Malignant - descriptor Malignant Neoplasms Marrow Mediating Modification Participant Patients Peripheral Blood Mononuclear Cell Phase Phase II Clinical Trials Plasmid Cloning Vector Positioning Attribute Procedures Quality Control Recurrent disease Relapse Relative (related person)Research Research Personnel Residual Neoplasm Safety Sampling Series Signal Transduction Specimen Suicide Surface System T-Cell Immunologic Specificity T-Lymphocyte Technology Therapeutic Toxic effect Transgenes Translations Transplant Recipients Transplantation Treatment Protocols Tumor Antigens Tumor-Derived Umbilical Cord Blood Umbilical Cord Blood Transplantation University of Texas M D Anderson Cancer Center Viral cellular targeting clinical application cohort conditioning design functional status high risk in vivo leukemia leukemia/lymphoma lymph nodes mortality peripheral blood programs response trafficking transgene expression tumor vector

项目摘要

DESCRIPTION (provided by applicant): The studies address the problem of relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after umbilical cord blood transplant (UCBT). We hypothesize that the incidence of relapse following allogeneic UCBT can be reduced by targeting post-transplant minimal residual disease (MRD) with adoptively transferred donor-derived leukemia-specific T-cells. As a strategy to reproducibly generate effector cells for adoptive therapy after UCBT, we have designed a new chimeric antigen receptor (CAR), designated CD19RCD28, which re-directs the antigen specificity of T cells to the B-cell lineage-restricted cell-surface molecule CD19. Genetically-modified CD19-CAR* cytotoxic T lymphocytes (CTL's) are activated through chimeric CD28 and CD3, and lyse B-cell malignant target cells in a CAR-regulated manner. T-cell isolation, genetic modification, and expansion Standard Operating Procedures at MDACC will manufacture clinical cell doses in accordance with quality control/assurance standards mandated by the FDA. The studies proposed in Specific Aim #1 will evaluate the feasibility and safety of adoptive therapy using three escalating doses (108/m2-1010/m2) of donor-derived CD19RCD28+HyTK+ CTL-clones versus oligoclonal/polyclonal T-cell lines, after reduced intensity allogeneic UCBT for high-risk CD19* B-ALL. We hypothesize that the lymphodepleting preparative regimen will promote homeostatic proliferation of transferred T-cells, as well as, limit anti-transgene rejection responses. The correlative studies in Specific Aim #2 focus on delineating the magnitude and duration of persistence of transferred clones versus lines at the three prescribed T-cell dose levels using vector-specific Q-PCR and TCR spectratyping analyses on serially acquired PBMC specimens. We will also evaluate the utility of administering recombinant human IL-2 for enhancing the expansion of transferred T-cells in vivo. The correlative studies proposed in Specific Aim 3 will evaluate the bone marrow and lymph node trafficking of transferred clones versus lines, and, the functional status of transferred T-cells in these anatomic sites of B-ALL MRD. In aggregate, the results of the studies proposed will facilitate the evolution of targeting post-UCBT MRD with CD19-specific T-cells for enhanced disease-free survival of patients with B-lineage ALL, and substantiate the rationale to expand this approach to a broader array of CD19+ malignancies treated by HCT.

描述（由申请人提供）：该研究解决了脐带血移植（UCBT）后B系急性淋巴细胞白血病（B-ALL）复发的问题。我们假设，通过过继转移供体来源的白血病特异性 T 细胞来靶向移植后微小残留病 (MRD)，可以降低同种异体 UCBT 后复发的发生率。作为 UCBT 后可重复生成用于过继治疗的效应细胞的策略，我们设计了一种新的嵌合抗原受体 (CAR)，命名为 CD19RCD28，它将 T 细胞的抗原特异性重新定向到 B 细胞谱系限制的细胞表面分子CD19。基因修饰的 CD19-CAR* 细胞毒性 T 淋巴细胞 (CTL) 通过嵌合 CD28 和 CD3 被激活，并以 CAR 调节的方式裂解 B 细胞恶性靶细胞。 MDACC 的 T 细胞分离、基因改造和扩增标准操作程序将根据 FDA 规定的质量控制/保证标准生产临床细胞剂量。具体目标#1中提出的研究将评估使用三种递增剂量（108/m2-1010/m2）的供体来源的 CD19RCD28+HyTK+ CTL 克隆与寡克隆/多克隆 T 细胞系进行过继治疗的可行性和安全性。针对高危 CD19* B-ALL 的降低强度同种异体 UCBT。我们假设淋巴细胞清除准备方案将促进转移 T 细胞的稳态增殖，并限制抗转基因排斥反应。具体目标 #2 中的相关研究重点是使用对连续采集的 PBMC 样本进行载体特异性 Q-PCR 和 TCR 光谱分析，描绘在三个指定 T 细胞剂量水平下转移克隆与细胞系的持久性程度和持续时间。我们还将评估施用重组人 IL-2 对于增强转移的 T 细胞体内扩增的效用。具体目标 3 中提出的相关研究将评估转移克隆与细胞系的骨髓和淋巴结运输，以及转移 T 细胞在 B-ALL MRD 解剖部位的功能状态。总的来说，所提出的研究结果将促进用 CD19 特异性 T 细胞靶向 UCBT 后 MRD 的发展，以提高 B 系 ALL 患者的无病生存率，并证实将这种方法扩展到HCT 治疗的 CD19+ 恶性肿瘤范围更广。