Specific Adoptive Immunotherapy of Leukemia

白血病的特异性过继免疫治疗

• 批准号: 8277821
• 负责人: PHILIP D GREENBERG
• 金额: $ 57.97万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277821
• 关键词: Address; Adoptive Immunotherapy; Aftercare; Allogenic; Antigens; Back; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cells; Characteristics; Frequencies; Hematopoietic Stem Cell Transplantation; Immune system; Immunotherapy; In Vitro; Laboratories; Leukemic Cell; Mediating; Memory; Methods; Nature; PRTN3 gene; Patients; Phenotype; Population Heterogeneity; Proteinase 3; Proteins; Public Health; Relapse; Research; Risk; Specificity; T cell response; T-Lymphocyte; Therapeutic; Toxic effect; Transplantation; Vaccines; WT1 gene; adult leukemia; immunogenic; improved; in vivo; leukemia; overexpression; response; tumor

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.

但前提是。 5.白血病的特异性过继免疫治疗 T细胞在体内介导抗肿瘤作用的能力现在已经得到了很好的证明，特别是在 异基因造血干细胞移植(HSCT)治疗白血病。然而，可重复性地 要使这一活动提供治疗益处，需要确定白血病所表达的抗原 具有免疫原性的细胞，可以安全地靶向，对宿主没有毒性，这是性质的特征 以及根除白血病所需的T细胞反应的大小，以及开发实现 患者的这种反应。我们的实验室一直在通过研究收养T细胞来解决这些问题 治疗，一种从血液中分离出与选定抗原有潜在反应的T细胞的策略， 对抗原致敏并在体外大量扩增，然后回输给患者。这 该方法克服了限制疫苗策略的许多障碍，并允许关键变量 控制和操纵，包括体内反应的大小和表型 以及肿瘤反应性T细胞的功能，使得在一小群患者中确定- 以蛋白质为靶点的治疗潜力和风险，并定义必须达到的参数 疫苗将会成功。我们选择的靶向抗原WT1和蛋白水解酶3过度表达 通过白血病细胞，有助于白血病表型，并能够诱导T细胞反应。这个 拟议的研究还将探索建立有效的CD4*的治疗活性和潜在风险。 作为CDS*T细胞对白血病抗原的反应。具体目标是：。 。1)确定供者来源的针对WT1或PR3的CD8*T细胞克隆是否转移到 异基因造血干细胞移植后的晚期白血病或MDS是安全的，并能发挥抗肿瘤作用。 2)确定WT1特异性的CD4+T细胞克隆是否可以从不同的MHC中重复生成 正常供者群体，以及供者来源的CD4+T细胞克隆是否转移到晚期患者 异基因造血干细胞移植后的白血病是安全的，可以持续存在，并能发挥抗肿瘤作用。。‘。 3)开发方法，以潜在地提高持久性和长期治疗活性 转移白血病反应性CD8+T细胞，不仅产生效应性T细胞，而且还产生T细胞 中央记忆细胞特有的表型/功能。 研究与公共健康的相关性：异基因治疗后白血病复发的频率 造血干细胞移植要求开发更多的治疗方法。这些研究将 利用免疫系统良好的特异性，在移植后选择性地靶向白血病细胞，以及 将制定将这种免疫疗法有效地应用于更广泛的治疗环境的原则。