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

描述（由申请人提供）：无关脐带血移植（UCBT）后死亡的一个重要原因是潜在恶性肿瘤复发。虽然输注肿瘤特异性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）效应并降低接受骨髓或外周血来源的造血祖细胞异基因移植的患者的复发率，但脐带血（UCB）供体的匿名性迄今为止已经排除了UCBT后过继免疫治疗的应用。为了克服这一限制，我们已经从UCB中产生了对CD19特异性的T细胞，CD19是一种通常在B系白血病和淋巴瘤中表达的分子。对CD19的特异性来源于在遗传修饰的T细胞的细胞表面上表达的嵌合免疫受体，该受体将CD19的抗体识别与通过嵌合CD3-？活化的T细胞的效应器功能相结合。该资助计划通过评估三种方法来提高这些UCB衍生的CD19特异性T细胞的治疗潜力，以改善其在体内的持久性，从而提高过继转移后的抗肿瘤作用。(1)体外扩增的遗传操作的CD8 + T细胞在体内依赖于T细胞帮助，其可以由外源性IL-2提供，以维持增殖和存活。因此，CD19特异性T细胞将与CD10特异性-IL2免疫细胞因子（ICK）组合，以便在CD19 + CD10 + B系恶性肿瘤的微环境中的CD10结合位点协调辅助性T细胞（Th）应答的递送。(2)基因修饰的CD19特异性CD4 + T细胞是抗原特异性帮助的潜在来源。因此，将评估UCB来源的CD4 + T细胞作为CD8 + CD19特异性T细胞的Th活性来源。(3)T细胞的完全活性活化导致其增殖和存活需要通过抗原受体和次级共刺激分子两者的协调信号传导。因此，CD19特异性嵌合免疫受体将被修饰以提供遗传修饰的CD4+和CD8 + T细胞，在与B7-CD19+恶性靶标接合后，通过CD28串联活化和共刺激。这些数据将有助于设计使用过继免疫治疗的临床方案，以增强GVL效应，不仅在UCBT后，而且在一般异基因造血干细胞移植后。非专业人士：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，该基金建议从脐带血中产生肿瘤特异性T细胞，并评估其用于免疫治疗的潜力。

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.