Leukemia Immunotherapy After Allogeneic Transplant

描述（由申请人提供）：本研究的目的是使用异基因造血干细胞（HSC）移植的小鼠模型来鉴定可用于设计治疗方案的免疫学机制，该治疗方案将降低白血病儿童异基因HCS移植后白血病复发的可能性。在异基因造血干细胞移植中，移植物抗白血病（GVL）效应与GVHD密切相关，临床上试图将两者分开并不成功。在缺乏特异性免疫操作的情况下，移植后产生的显性同种异体免疫应答针对免疫显性的、广泛分布的宿主抗原，并且移植后环境不利于产生对最小残留白血病抗原具有相对选择性的免疫应答。申请人的实验室最近证明，在移植后用细胞肿瘤疫苗治疗的同种异体HSC移植受体表现出延长的存活，但不经历GVHD的恶化。这种疫苗的作用机制正在研究中。假设：移植后肿瘤疫苗可以增强全身免疫应答，可以控制微小残留白血病，而不会加重临床上显著的移植物抗宿主病。 具体目标1：验证异基因造血干细胞移植后，特异于亚显性次要组织相容性抗原的中等亲和力T细胞可被疫苗激活以发挥抗白血病活性而不发生GVHD的假设。 具体目标二：为了验证这一假设，即异基因延迟淋巴细胞输注治疗急性淋巴细胞恶性肿瘤可以通过同时接种白血病相关抗原而变得更有效。 具体目标3：鉴定移植后肿瘤疫苗诱导的T细胞的白血病相关抗原靶标，并确定这些凭经验鉴定的基因是否与基于基因表达分析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.