Project 3: Tumor Antigen Reactive Donor T Cell Immunotherapy

项目3：项目摘要/摘要 拟议研究的目的是确定MHC捐献者的肿瘤抗原疫苗接种是否匹配 造血细胞移植(HCT)可以在不增加移植物抗肿瘤(GVT)活性的情况下增加移植物抗肿瘤(GVT)活性。 临床前和临床研究中的抗宿主病(GVHD)。对于B细胞淋巴瘤，我们将 用B细胞受体(BCR)CDR3区独特型多肽疫苗免疫 肿瘤。对于髓系白血病，我们将使用WT-1肽进行疫苗接种，WT-1肽是一种 过表达的白血病肿瘤抗原。患有B细胞淋巴瘤的小鼠和人类受者将被条件 使用全淋巴照射和抗胸腺细胞抗体(一种急性移植物抗宿主病保护方案)，并混合 嵌合体将接受介导GVT的表型CD8+Memory T(TM)细胞供者淋巴细胞输注(DLI) 没有来自独特型免疫供者的GVHD。分离的CD8+TM细胞表达CD8+CD44hi表型 人CD8+CD45R0+CD45RA-表型。还预计DLI将导致转换 从混合嵌合体到完全嵌合体，肿瘤抗原免疫的TM细胞DLI将介导强大的GVT 与未免疫的TM细胞DLI的活性相比较。预计接受者的加强疫苗接种将会增加 抗肿瘤活性进一步增强。给予髓系白血病移植受者GVHD将降至最低 T细胞耗竭CD34+选择的移植物联合供者CD8+TM的清髓性预适应 细胞。后一种细胞的输注有望改善免疫重建和GVT活性。 至TCD CD34+选定移植物。总而言之，我们将使用我们实验室制定的策略来防止 GVHD和肿瘤抗原免疫以增加GVT活性，从而使总体和无事件生存 在拟议的临床前和临床研究中有所增加。

Project 3: Project Summary/Abstract The object of the proposed studies is to determine whether tumor antigen vaccination of donors of MHC matched hematopoietic cell transplants (HCT) can increase graft-versus-tumor (GVT) activity without increasing graft- versus-host disease (GVHD) in both pre-clinical and clinical studies. In the case of B cell lymphomas, we will use vaccination with idiotype peptides derived from the B-cell receptor (BCR) CDR3 region to immunize against the tumors. In the case of myeloid leukemia, we will use vaccination with the WT-1 peptide that is an overexpressed leukemia tumor antigen. Mouse and human recipients with B cell lymphoma will be conditioned with total lymphoid irradiation and anti-thymocyte antibodies (an acute GVHD protective regimen), and mixed chimeras will receive phenotypic CD8+ memory T (TM) cell donor lymphocyte infusions (DLI) that mediate GVT without GVHD from idiotype immunized donors. Sorted CD8+ TM cells express the CD8+CD44hi phenotype in mice, and CD8+CD45R0+CD45RA- phenotype in humans. It is also expected that the DLI will induce conversion from mixed to complete chimerism, and that the tumor antigen immunized TM cell DLI will mediate potent GVT activity as compared to the nonimmunized TM cell DLI. Booster vaccinations of recipients is expected to increase anti-tumor activity even further. GVHD will be minimized in myeloid leukemia transplant recipients given myeloablative conditioning by using T cell depleted (TCD) CD34+ selected grafts combined with donor CD8+ TM cells. The infusion of the latter cells is expected to improve immune reconstitution and GVT activity as compared to TCD CD34+ selected grafts alone. In summary, we will use strategies developed in our laboratory to prevent GVHD, and tumor antigen immunization to increase GVT activity such that overall and event-free survival is increased in the proposed preclinical and clinical studies.