Specific Adoptive Immunotherapy of Leukemia

白血病的特异性过继免疫治疗

• 批准号: 7792294
• 负责人: PHILIP D GREENBERG
• 金额: $ 63.49万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7792294
• 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-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.

假如。 5。白血病的特定收养免疫疗法 如今，T细胞介导体内抗肿瘤效应的能力已有据可查，尤其是在情况下 白血病的同种异体造血干细胞移植（HSCT）但是，可重复 纳入这项活动以提供治疗益处，需要确定白血病表达的抗原 免疫原性的细胞可以安全地靶向无毒性，表征性质 消除白血病所需的T细胞反应的大小和开发方法以实现 患者的这种反应。我们的实验室一直通过追求收养T细胞来解决这些问题 治疗，一种策略，其中T细胞可能从血液中分离出可能与选定抗原反应性的T细胞， 对抗原敏感并在体外扩展到大量，并将其注入患者。这 方法克服了许多限制疫苗策略的障碍，并允许关键变量为 受控和操纵，包括实现的体内反应的大小和表型 和肿瘤反应性T细胞的功能，使一小组患者在确定 - 治疗潜力和靶向蛋白质的风险并定义必须实现的参数 疫苗成功。我们选择的抗原靶向WT1和蛋白酶3，过表达 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 拟议的研究还将探讨建立有效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。具体目的是：。 。 1）确定供体衍生的CD8* T细胞克隆是否针对WT1或PR3转移到患者中 同种异体HSCT后，晚期白血病或MDS是安全的，可以介导抗肿瘤作用。 2）确定是否可以从MHC多样性地重复产生特定于WT1的CD4+ T细胞克隆 正常供体的人口。 同种异体HSCT后的白血病是安全的，可以持续存在，并且可以介导抗肿瘤作用。 。 '。 3）开发方法，以改善 转移白血病反应性CD8+ T细胞不仅通过产生效应T细胞，还产生具有的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：同种异体治疗后白血病复发的频率 造血干细胞移植决定了其他疗法。这些研究会 利用免疫系统的良好特异性在移植后选择性靶向白血病细胞，并 将制定有效将这种免疫疗法应用于更广泛治疗环境的原则。