Specific Adoptive Immunotherapy of Leukemia

提供了 5.白血病的特异性免疫治疗 T细胞介导体内抗肿瘤作用的能力现在已经得到充分的证明，特别是在 异基因造血干细胞移植（HSCT）治疗白血病。然而，可重复地 说明这种活性以提供治疗益处需要鉴定白血病表达的抗原 具有免疫原性并且可以安全靶向而对宿主无毒性的细胞，表征了 以及根除白血病所需的T细胞反应的大小，并开发实现 患者的这种反应。我们的实验室一直致力于解决这些问题， 治疗，一种从血液中分离与选定抗原潜在反应的T细胞的策略， 对抗原致敏并在体外大量扩增，然后输注回患者体内。这 这种方法克服了许多限制疫苗策略的障碍，并允许关键变量被 控制和操纵，包括体内反应的大小和表型 和肿瘤反应性T细胞的功能，使其有可能在一小群患者中确定- 靶向蛋白质的治疗潜力和风险，并定义必须达到的参数， 疫苗是成功的。我们选择的靶抗原WT 1和蛋白酶3过表达 由白血病细胞，有助于白血病表型，并能够诱导T细胞反应。的 拟议的研究将探索建立有效的CD 4 * 的治疗活性和潜在风险， CD 4 + T细胞对白血病抗原的反应。具体目标是： . 1)确定WT 1或PR 3特异性的供体来源的CD 8 * T细胞克隆是否转移到患有 异基因HSCT后的晚期白血病或MDS是安全的，并且可以介导抗肿瘤作用。 2)确定WT 1特异性的CD 4 + T细胞克隆是否可以从MHC多样性细胞中可重复地产生。 如果将供体来源的CD 4 + T细胞克隆转移到晚期乳腺癌患者中， 异基因HSCT后白血病是安全的，可以持续存在，并可以介导抗肿瘤作用。. '. 3)开发可能改善药物持久性和长期治疗活性的方法 通过不仅产生效应T细胞，而且产生T细胞转移白血病反应性CD 8 + T细胞， 中央记忆细胞的表型/功能特征。 研究与公共卫生的相关性：白血病患者接受同种异体化疗后复发的频率 造血干细胞移植要求开发其他疗法。这些研究将 在移植后利用免疫系统的良好特异性选择性靶向白血病细胞， 将制定有效地将这种免疫疗法应用于更广泛的治疗环境的原则。

PROVIDED. 5. Specific Adoptive Immunotherapy of Leukemia The ability of T cells to mediate in vivo anti-tumor effects is now well-documented, particularly in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia. However, reproducibly narnessing this activity to provide therapeutic benefit requires identifying antigens expressed by leukemia cells that are immunogenic and can be safely targeted without toxicity to the host, characterizing the nature and magnitude of the T cell responses required to eradicate leukemia, and developing methods to achieve such responses in patients. Our laboratory has been addressing these issues by pursuing adoptive T cell therapy, a strategy in which T cells potentially reactive with a selected antigen are isolated from the blood, sensitized to the antigen and expanded in vitro to large numbers, and infused back into the patient. This approach overcomes many obstacles that limit vaccine strategies, and permits critical variables to be controlled and manipulated, including the magnitude of the in vivo response achieved and the phenotype and function of the tumor-reactive T cells, making it possible in a small set of patients to determine the - therapeutic potential and risks of targeting a protein and to define the parameters that must be achieved for a vaccine to be successful. The antigens we have chosen to target, WT1 and Proteinase 3, are overexpressed by leukemic cells, contribute to the leukemic phenotype, and are capable of inducing T cell responses. The proposed studies will explore the therapeutic activity and potential risks of establishing potent CD4* as well as CDS* T cell responses to leukemia antigens. The specific aims are to: . . 1) Determine if donor-derived CD8* T cell clones specific for WT1 or PR3 transferred into patients with advanced leukemia or MDS after allogeneic HSCT is safe and can mediate an antitumor effect. 2) Determine if CD4+ T cell clones specific for WT1 can be reproducibly generated from an MHC diverse population of normal donors, .and if donor-derived CD4+ T cell clones transferred into patients with advanced leukemia after allogeneic HSCT are safe, can persist, and can mediate an antitumor effect. . '. 3) Develop methods to potentially improve the persistence and long-term therapeutic activity of transferred leukemia-reactive CD8+ T cells by generating not only effector T cells but also T cells with phenotypes/functions characteristic of central memory cells. Relevance of research to public health: The frequency of leukemic relapse after treatment with allogeneic hematopoietic stem cell transplantation dictates that additional therapies be developed. These studies will utilize the fine specificity of the immune system to selectively target leukemia cells after transplantation, and will develop principles for effectively applying such immunotherapy to broader treatment settings.