Leukemia Immunotherapy After Allogeneic Transplant

描述(申请人提供)：这项研究的目标是使用异基因造血干细胞(HSC)移植的小鼠模型来确定可用于设计降低白血病儿童异基因HCS移植后白血病复发可能性的治疗方法的免疫学机制。在异基因造血干细胞移植中，移植物抗白血病(GVL)效应与移植物抗白血病(GVHD)密切相关，临床上将两者分开的尝试并不成功。在缺乏特异性免疫操作的情况下，移植后产生的主要同种异体免疫反应是针对免疫优势的、分布广泛的宿主抗原，移植后的环境不利于免疫反应的发展，相对选择性地针对微小残留白血病的抗原。申请人的实验室最近证明，移植后使用细胞肿瘤疫苗治疗的异基因HSC移植接受者表现出更长的存活时间，但没有GVHD恶化。这种疫苗作用的机制正在调查中。假设：移植后的肿瘤疫苗可以增强系统免疫反应，可以控制微小的残留白血病，而不会加剧临床上有意义的移植物抗宿主病。 具体目的1：验证异基因造血干细胞移植后，疫苗可以激活针对亚型次要组织相容性抗原的中等亲和力T细胞发挥抗白血病活性的假说，而不需要GVHD。 特定目的2：验证通过同时接种白血病相关抗原疫苗可使异基因延迟淋巴细胞输注治疗急性淋巴母细胞恶性肿瘤更有效的假说。 具体目的3：确定移植后肿瘤疫苗诱导的T细胞的白血病相关抗原靶点，并根据基因表达分析确定这些经验性识别的基因是否与预测为抗原性的基因类别相关。

DESCRIPTION (provided by applicant): The goal of this research is to use murine models of allogeneic hematopoietic stem cell (HSC) transplantation to identify immunological mechanisms that can be used to design therapies that will reduce the likelihood of leukemia relapse after allogeneic HCS transplant in children with leukemia. In allogeneic HSC transplant the graft versus leukemia (GVL) effect is closely associated with GVHD and clinical attempts to separate the two have not been successful. In the absence of specific immune manipulation the dominant allogeneic immune response that develops after transplant is directed at immunodominant, widely distributed host antigens, and the post-transplant environment does not favor development of immune responses with relative selectively for antigens on minimal residual leukemia. The applicant's laboratory has recently demonstrated that allogeneic HSC transplant recipients treated after transplant with cellular tumor vaccines exhibit prolonged survival but do not experience exacerbations of GVHD. The mechanism of this vaccine effect is under investigation. Hypothesis: Post-transplant tumor vaccines can enhance systemic immune responses that can control minimal residual leukemia without exacerbation of clinically significant graft versus host disease. Specific Aim 1: To test the hypothesis that after allogeneic hematopoietic stem cell transplantation moderate affinity T cells specific for subdominant minor histocompatibility antigens can be activated by vaccines to exert antileukemia activity without GVHD. Specific Aim 2: To test the hypothesis that allogeneic delayed lymphocyte infusion for acute lymphoblastic malignancies can be made more effective by simultaneous vaccination against leukemia associated antigens. Specific Aim 3: To identify the leukemia associated antigenic targets of T cells induced by post-transplant tumor vaccines and to determine if these empirically identified genes correlate with classes of genes predicted to be antigenic based on gene expression analysis.