T-CELLS AND TRANSPLANTATION THERAPIES

T 细胞和移植疗法

• 批准号: 3204950
• 负责人: JAMES E TALMADGE
• 金额: $ 14.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3204950
• 关键词: T lymphocyte; autologous transplantation; bone marrow purging; bone marrow transplantation; cell mediated lymphocytolysis test; cytokine; flow cytometry; gene expression; hematopoietic stem cells; human subject; human therapy evaluation; leukapheresis; natural killer cells; neoplasm /cancer immunotherapy; neoplastic process; nonHodgkin's lymphoma; phenotype; polymerase chain reaction; statistics /biometry

Bone marrow transplantation (BMT) has allowed the treatment of cancer patients with more intensive protocols of chemo/radiotherapy, thereby decreasing the incidence of relapse. The use of peripheral blood derived mononuclear cells in place of bone marrow has gained acceptance in those patients for whom BMT is not an option. In a retrospective analysis at the University of Nebraska Medical Center patients with intermediate grade non-Hodgkin's lymphoma (NHL) receiving high dose therapy with autologous BMT (AuBMT) (n=105) had a three-year event free survival (EFS) of 24%. This compares to a three-year EFS of 38% for patients with intrinsic bone marrow abnormalities who underwent high dose therapy with peripheral blood stem cell transplant (PBSCT) (n=53). We hypothesize that patients receiving a PBSCT would have an improved response rate, and T cell activity due to the infusion of greater numbers of mature T cells relative to BMT. Although the hematopoietic reconstitution of these patients has been described, little data has been obtained on their immune reconstitution. Thus, it is the overall intent of this proposal to examine the reconstitution of the immune system after PBSCT and compare the reconstitution observed after PBSCT to that observed after AuBMT and determine if this has a role in the therapeutic response of the PBSCT patients. The overall pattern of immune reconstitution in patients receiving PBSCT will be compared to that in patients receiving AuBMT to determine whether significant differences exist between these two groups of patients in either the extent, pattern, timing or longevity of this reconstitution and to correlate T cell reconstitution with clinical disease progression or lack thereof. Based on preliminary results in both preclinical and clinical studies, the hypothesis to be tested in this application is that PBSCT has significantly greater potential (compared to AuBMT) to reconstitute lymphocyte populations both phenotypically and functionally (especially T lymphocytes) after marrow ablative therapy with improved therapeutic activity. This hypothesis will be tested by examining the phenotypic, functional and molecular characteristics of peripheral blood lymphocytes in patients undergoing each therapy. Further, in conjunction with the clinical portion of this interactive RO1, we will correlate the various surrogates of immune function with EFS, time to disease progression, sites of relapse and survival to provide some insight into the therapeutic impact of functional T cells.

骨髓移植（BMT）允许治疗癌症 具有更密集的化学/放射治疗方案的患者，从而 降低复发的发生率。衍生的外周血的使用 单核细胞代替骨髓已在那些 BMT不是一个选择的患者。在回顾性分析中 内布拉斯加州大学医学中心中级患者 非霍奇金的淋巴瘤（NHL）接受自体的高剂量疗法 BMT（AUBMT）（n = 105）的三年无事件生存期（EFS）为24％。 相比之下，固有骨患者的三年EFS为38％ 骨髓异常接受高剂量治疗的外周血液 干细胞移植（PBSCT）（n = 53）。我们假设患者 接收PBSCT将具有提高的响应率，并且T细胞 由于输注更多成熟的T细胞相对相对的活性 到BMT。尽管这些患者的造血重构已有 被描述了，几乎没有获得有关其免疫的数据 重组。因此，这项提议的总体意图是检查 PBSCT之后的免疫系统的重建，并比较 PBSCT之后观察到的重建，并在AUBMT和 确定这是否在PBSCT的治疗反应中起作用 患者。患者免疫重建的总体模式 接收PBSCT将与接受AUBMT的患者进行比较 确定这两组之间是否存在显着差异 患者在此的程度，模式，时机或寿命的程度上 重构并将T细胞重构与临床相关联 疾病进展或缺乏疾病。基于两者的初步结果 临床前和临床研究，在此要检验的假设 应用是PBSCT具有明显更大的潜力（与 AUBMT）在表型和 在功能上（尤其是T淋巴细胞）在骨髓消融治疗后与 改善治疗活性。该假设将通过检查 外周的表型，功能和分子特征 接受每种治疗的患者的血液淋巴细胞。此外，在 与此交互式RO1的临床部分结合，我们将 将免疫功能的各种替代物与EFS相关联 疾病进展，复发和生存部位，以提供一些见识 进入功能性T细胞的治疗影响。