Enhancing the efficacy of CD19-specific cord blood-derived T Cells

描述(申请人提供)：无血缘关系的脐带血移植(UCBT)后死亡的一个重要原因是潜在恶性肿瘤的复发。对于接受骨髓或外周血造血祖细胞异基因移植的患者来说，输注肿瘤特异性T细胞在概念上是一种有吸引力的策略，可以增强移植物抗白血病(GVL)效应并降低复发率，但脐带血(UCB)捐赠者的匿名性到目前为止阻止了UCBT后过继免疫治疗的应用。为了克服这一限制，我们从脐带血中产生了针对CD19的T细胞，CD19是一种在B系白血病和淋巴瘤上常见表达的分子。CD19的特异性来源于表达在转基因T细胞表面的嵌合免疫受体，它结合了CD19的抗体识别和通过嵌合CD3-？激活的T细胞的效应功能。这笔赠款建议通过评估三种方法来提高这些脐带血来源的CD19特异性T细胞的治疗潜力，以改善它们在体内的持久性，从而在过继转移后发挥抗肿瘤作用。(1)体外扩增的基因操作的CD8+T细胞在体内依赖T细胞的帮助，外源性IL-2可以提供这种帮助来维持增殖和生存。因此，CD19特异的T细胞将与CD10特异的IL2免疫细胞因子(ICK)结合，以协调CD19+CD10+B系肿瘤微环境中CD10结合部位的T辅助(Th)应答的传递。(2)基因修饰的CD19特异性的CD4+T细胞是抗原特异性帮助的潜在来源。因此，脐带血来源的CD4+T细胞将被评估为CD8+CD19特异性T细胞的Th活性的来源。(3)T细胞的充分激活导致其增殖和存活，需要通过抗原受体和次级共刺激分子的协调信号。因此，CD19特异性嵌合免疫受体将被修饰，以提供转基因的CD4+和CD8+T细胞，在与B7-CD19+恶性靶点结合时，通过CD28串联激活和共刺激。这些数据将有助于设计临床方案，使用过继免疫疗法来增强GVL效应，不仅在UCBT之后，而且在异基因造血干细胞移植后也是如此。俗语：输注来自脐带血的肿瘤特异性T细胞可能会降低脐带血移植后的复发率。因此，这笔赠款建议从脐带血中产生肿瘤特异性T细胞，并评估其免疫治疗的潜力。

DESCRIPTION (provided by applicant): A significant cause of mortality after unrelated umbilical cord blood transplant (UCBT) is due to recurrence of the underlying malignancy. While infusion of tumor-specific T cells is a conceptually attractive strategy to enhancing graft-versus-leukemia (GVL)-effect and reducing relapse rates for patients undergoing allogeneic transplant with marrow- or peripheral blood-derived hematopoietic progenitor cells, the anonymity of the umbilical cord blood (UCB) donor has so far precluded this application of adoptive immunotherapy after UCBT. To overcome this limitation, we have generated T cells from UCB that are specific for CD19, a molecule commonly expressed on B-lineage leukemias and lymphomas. The specificity for CD19 is derived from a chimeric immunoreceptor expressed on the cell surface of genetically modified T cells that combines antibody-recognition of CD19 with the effector-function of T cells activated through chimeric CD3-?. This grant proposes to enhance the therapeutic potential of these UCB-derived CD19-specific T cells by evaluating three approaches to improving their in vivo persistence, and therefore anti-tumor effect, after adoptive transfer. (1) Ex vivo-expanded genetically manipulated CD8+ T cells are dependent in vivo on T-cell help, which can be provided by exogenous IL-2, to sustain proliferation and survival. Therefore, CD19-specific T cells will be combined with CD10-specific-IL2 immunocytokine (ICK) in order to coordinate delivery of a T-helper (Th) response at sites of CD10-binding in the microenvironment of CD19+CD10+ B-lineage malignancies. (2) Genetically modified CD19-specific CD4+ T cells are a potential source of antigen-specific help. Therefore, UCB-derived CD4+ T cells will be evaluated as a source of Th activity for CD8+ CD19- specific T cells. (3) Fully-competent activation of T cells resulting in their proliferation and survival requires coordinated signaling through both an antigen receptor and secondary co-stimulator molecules. Therefore, the CD19-specific chimeric immunoreceptor will be modified to provide genetically modified CD4+ and CD8+ T cells, with tandem activation and co-stimulation through CD28, upon engagement with B7-CD19+ malignant targets. These data will facilitate the design of clinical protocols using adoptive immunotherapy to enhance the GVL-effect, not just after UCBT, but also after allogeneic hematopoietic stem-cell transplants in general. Lay language: Infusing tumor-specific T cells derived from cord blood may reduce relapse rates after umbilical cord blood transplant. This grant therefore proposes to generate tumor specific T cells from cord blood and evaluate their potential for immunotherapy.