Adoptive immunotherapy after umbilical cord blood transplant

脐带血移植后的过继免疫治疗

• 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
• 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

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。作为在 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在对高风险 CD19* B-ALL 进行降低强度同种异体 UCBT 后，使用三种递增剂量 (108/m2-1010/m2) 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。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 治疗的更广泛的 CD19+ 恶性肿瘤的基本原理。