HSV-1 TK MODIFIED T CELLS FOR GRAFT VERSUS LEUKEMIA

HSV-1 TK 修饰 T 细胞用于移植物抗白血病

• 批准号: 6242492
• 负责人: STEVEN EMERSON
• 金额: $ 35.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242492
• 关键词: T lymphocyte; blood treatment; bone marrow transplantation; chronic myelogenous leukemia; disease /disorder model; ganciclovir; genetically modified animals; graft versus host disease; herpes simplex virus 1; histocompatibility; homologous transplantation; human subject; laboratory mouse; leukocyte transfusion; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; thymidine kinase; transfection; transplant rejection; transplantation immunology

Cellular transfusion therapies in the past have been limited to erythrocytes, platelets, stem cells from a variety of sources, and rarely neutrophils. We propose to develop the relevant preclinical data base for the use of T lymphocytes as a safe and effective transfusion therapy for the eradication of residual leukemia. Graft-versus host disease (GVHD) and its accompanying Graft-versus-leukemia (GVL) effect contribute to the efficacy of allogeneic bone marrow transplantation (alloBMT) in treating hematologic malignancies. In patients who have relapsed after alloBMT for chronic myelogenous leukemia (CML), both the withdrawal of immunosuppression and more recently that infusion of infusion of pheresed lymphocyts have led to complete cytogenetic remissions, but with significant morbidity from GVHD. This raises the possibility of an exciting new method for treatment of leukemias, and perhaps for other cancers. A key advance in maximizing the therapeutic potential of such therapy would be a way to in vivo modulate t he GVHD which is the equivalent of a dose limiting toxicity. We propose to accomplish this by the introduction into lymphocytes of the Herpes Simplex Virus thymidine kinase (HSV1-tk)gene, which by virtue of its ability to activate selectively the nucleoside analogue ganciclovir, will render them susceptible to ganciclovir deletion. To test this hypothesis, we will study the impact of HSV1-tk expressing lymphocytes and ganciclovir treatment on GVHD and GVL in well established murine models. In addition, we will develop techniques of efficient gene transfer and expression into both human and murine lymphocytes. The specific aims of this project are to: 1) Demonstrate that the GVHD induced by murine HSV-1tk expressing lymphocytes can be controlled with ganciclovir; 2) Establish relevant mouse models to test the efficacy of GVL induced by these transgenic lymphocytes, while maintaining adequate control of GVHD with ganciclovir; 3) Utilize HSV1-tk gene transfer into mouse lymphocytes, to compare efficacy between transgenic versus retrovirally transduced lymphocytes; 4) Develop techniques for HSV1-tk gene transfer and stable expression in human lymphocytes. The results of these studies will form the basis for well founded clinical studies using HSV1-tk transduced lymphocytes for the elimination of residual leukemia. In so doing, we believe that they will form the foundation for many future studies utilizing T cell transfusion therapies in the near future.

过去的细胞输血疗法仅限于 来自各种来源的红细胞、血小板、干细胞，并且很少 中性粒细胞。 我们建议开发相关的临床前数据库 使用 T 淋巴细胞作为一种安全有效的输血疗法 根除残留白血病。 移植物抗宿主病（GVHD）和 其伴随的移植物抗白血病（GVL）效应有助于 同种异体骨髓移植（alloBMT）治疗的疗效 血液系统恶性肿瘤。 异基因骨髓移植 (alloBMT) 后复发的患者 慢性粒细胞白血病（CML），两者都停药 免疫抑制和最近的输注 淋巴细胞已导致完全细胞遗传学缓解，但 GVHD 的显着发病率。 这增加了一种可能性 治疗白血病和其他疾病的令人兴奋的新方法 癌症。 最大化此类治疗潜力的关键进展 治疗将是体内调节 GVHD 的一种方法， 相当于剂量限制性毒性。 我们建议通过以下方式实现这一目标 将单纯疱疹病毒胸苷引入淋巴细胞 激酶 (HSV1-tk) 基因，凭借其激活能力 选择性地使用核苷类似物更昔洛韦，将使它们 对更昔洛韦缺失敏感。 为了检验这个假设，我们将 研究表达 HSV1-tk 的淋巴细胞和更昔洛韦的影响 在完善的小鼠模型中治疗 GVHD 和 GVL。 此外， 我们将开发高效的基因转移和表达技术 人类和小鼠淋巴细胞。 该项目的具体目标是 1) 证明小鼠 HSV-1tk 表达诱导 GVHD 淋巴细胞可用更昔洛韦控制； 2）建立相关 小鼠模型来测试这些转基因诱导的 GVL 的功效 淋巴细胞，同时用更昔洛韦维持对 GVHD 的充分控制； 3) 利用HSV1-tk基因转入小鼠淋巴细胞，进行比较 转基因淋巴细胞与逆转录病毒转染淋巴细胞之间的功效； 4） 开发 HSV1-tk 基因转移和在人体中稳定表达的技术 淋巴细胞。 这些研究的结果将成为良好的基础 建立了使用 HSV1-tk 转导淋巴细胞的临床研究 消除残留白血病。 通过这样做，我们相信他们会 为未来许多利用 T 细胞输注的研究奠定基础 在不久的将来进行治疗。