Adoptive immunotherapy after umbilical cord blood transplant

描述（由申请人提供）：这些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，通过过继转移供者来源的白血病特异性T细胞，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后可重复产生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CD 19 RCD 28，它将T细胞的抗原特异性重定向至B细胞谱系限制性细胞表面分子CD 19。遗传修饰的CD 19-CAR* 细胞毒性T淋巴细胞（CTL）通过嵌合的CD 28和CD 3活化，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、遗传修饰和扩增标准操作规程将根据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中拟定的研究将评价在对高危CD 19 * B-ALL进行降低强度的同种异体UCBT后，使用三种递增剂量（108/m2-1010/m2）的供体来源CD 19 RCD 28 +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的T细胞的稳态增殖，以及限制抗转基因排斥反应。特定目标#2中的相关研究侧重于使用载体特异性Q-PCR和TCR谱分析对连续采集的PBMC标本进行分析，描述在三种规定的T细胞剂量水平下转移克隆与细胞系的持续性的幅度和持续时间。我们还将评估施用重组人IL-2用于增强体内转移的T细胞的扩增的效用。具体目标3中提出的相关研究将评价转移克隆与系的骨髓和淋巴结运输，以及转移T细胞在B-ALL MRD这些解剖部位的功能状态。总体而言，拟定研究的结果将促进使用CD 19特异性T细胞靶向UCBT后MRD的发展，以提高B系ALL患者的无病生存期，并证实将该方法扩展至更广泛的CD 19+恶性肿瘤HCT治疗的基本原理。

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.