Adoptive immunotherapy after umbilical cord blood transplant

脐带血移植后的过继免疫治疗

• 批准号: 7486830
• 负责人: Laurence J.N. Cooper
• 金额: $ 29.26万
• 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: 2007-08-20 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486830
• 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; Numbers; Participant; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Phase; Phase II Clinical Trials; Plasmid Cloning Vector; Polymerase Chain Reaction; Positioning Attribute; Procedures; Quality Control; Recurrent disease; Relapse; Relative (related person); Research; Research Personnel; Residual Neoplasm; Risk; Safety; Sampling; Series; Signal Transduction; Specimen; Standards of Weights and Measures; 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; United States Food and Drug Administration; University of Texas M D Anderson Cancer Center; Viral; cellular targeting; clinical application; cohort; conditioning; design; functional status; 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）：研究解决了脐带血液移植（UCBT）后B-linege急性淋巴细胞白血病（B-All）复发的问题。我们假设，可以通过将移植后最小残留疾病（MRD）靶向以继承转移的供体衍生的白血病特异性T细胞来降低同种异体UCBT后复发的发生率。 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.遗传改性的CD19-CAR*细胞毒性T淋巴细胞（CTL）通过嵌合CD28和CD3激活，并以CAR调节的方式激活Lyse B细胞恶性靶细胞。 MDACC的T细胞隔离，遗传修饰和扩展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。特定目标＃1中提出的研究将使用三种供体衍生的CD19RCD28+ HYTK+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ hytk+ doungoclonal/polyclonal/polyclonal t-cell系列使用三种升级剂量（108/m2-1010/m2）的可行性和安全性。我们假设淋巴结的制备方案将促进转移的T细胞的稳态增殖，并限制抗转基因排斥反应。特定目标＃2中的相关性研究着重于在三个规定的T细胞剂量水平上使用矢量特异性Q-PCR和TCR频谱分析在三个规定的T细胞剂量水平上划定转移克隆与线的持久性和持续时间。我们还将评估管理重组人IL-2的实用性，以增强体内转移的T细胞的扩展。特定目标3中提出的相关研究将评估转移的克隆与线的骨髓和淋巴结运输，以及在B-all MRD的这些解剖部位中转移的T细胞的功能状态。总体而言，提出的研究结果将促进用CD19特异性T细胞靶向UCBT MRD的演变，以增强B-Linege患者的无疾病生存，并证实基本原理以将这种方法扩展到HCT治疗的CD19+ MALIGNANCERARAY。