Project 3: Tumor Antigen Reactive Donor T Cell Immunotherapy

项目3：项目概要/摘要 本研究的目的是确定肿瘤抗原疫苗接种的MHC供体是否匹配 造血细胞移植（HCT）可以增加移植物抗肿瘤（GVT）活性，而不增加移植物抗肿瘤活性。 抗宿主病（GVHD）在临床前和临床研究。对于B细胞淋巴瘤，我们将 使用来自B细胞受体（BCR）CDR 3区的独特型肽进行疫苗接种， 肿瘤在骨髓性白血病的情况下，我们将使用WT-1肽疫苗， 过表达白血病肿瘤抗原。将对患有B细胞淋巴瘤的小鼠和人受体进行调节 与全淋巴照射和抗胸腺细胞抗体（急性GVHD保护方案），并混合 嵌合体将接受介导GVT的表型CD 8+记忆T（TM）细胞供体淋巴细胞输注（DLI 没有来自独特型免疫供体的GVHD。分选的CD 8 + TM细胞表达CD 8 + CD 44 hi表型， 小鼠的CD 8 + CD 45 R 0 + CD 45 RA-表型。预计DLI还将促使转换 从混合嵌合到完全嵌合，并且肿瘤抗原免疫的TM细胞DLI将介导有效的GVT 与未免疫的TM细胞DLI相比，预计接种者的加强疫苗接种将增加 抗肿瘤活性更进一步。在骨髓性白血病移植受者中， 使用去除T细胞（TCD）的CD 34+选择性移植物联合供体CD 8 + TM的清髓性预处理 细胞预期输注后一种细胞将改善免疫重建和GVT活性， TCD CD 34+选择的移植物。总之，我们将使用我们实验室开发的策略来预防 GVHD和肿瘤抗原免疫以增加GVT活性，使得总体和无事件生存期延长。 在拟定的临床前和临床研究中增加。

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.