TUMOR VACCINES AFTER NON MYELOABLATIVE ALLOGRAFTING

S博士学位论文(申请人描述)：多种耐药菌 大剂量能有效地治疗肿瘤 放射治疗后的异基因骨髓移植 (AllBMT)，与免疫介导的移植物抗白血病相关 (GVL)效应。不幸的是，预适应方案的毒性，移植物抗宿主 疾病(GVHD)和复发是治疗失败的重要原因。非- 清髓异基因骨髓移植(NM AllBMT)是一种减少条件反射的新疗法 方案的强度和毒性，并作为诱发GVL的平台 供者淋巴细胞输注(DLI)的效果。这一点的中心假设是 建议通过以下方式增强NM allBMT的抗肿瘤效果 移植后给予肿瘤细胞疫苗+/-DLI，从而 绕过常见的内源性T细胞功能障碍 癌症患者。因此，具体目的是：1)审查 供受者组织不合，预适应方案 DLI对肿瘤疫苗免疫应答的强度和时机 异基因骨髓移植。2)表征肿瘤疫苗的效果 异基因骨髓移植后GVHD的给药及DLI的抗肿瘤作用3) 移植物抗宿主病和肿瘤疫苗对体内的影响 转基因T细胞的增殖、细胞因子产生及抗肿瘤作用 针对特定肿瘤抗原的细胞。 我的近期和长期目标是将肿瘤的实验室研究转化为 疫苗和异基因骨髓移植在临床上改进了癌症的治疗方法。我的 导师是Ephraim Fuchs博士和Drew Pardoll博士，他们在 翻译免疫学研究，并将支持我实现 独立调查员身份。约翰斯的所有癌症免疫学研究 霍普金斯大学在新的本廷-布劳斯坦癌症医院的四楼进行 研究大楼，提供最先进的设备和肥沃的 智力环境。约翰霍普金斯肿瘤中心有几个 肿瘤疫苗在实体和血液系统恶性肿瘤的临床试验， 每年进行200多例骨髓移植，大约一半 雇佣同种异体捐献者。

D E S C RIPTION (Applicant's Description): A variety of drug-resistant h e m atologic malignancies are effectively treated by high dose c h e m oradiotherapy followed by allogeneic bone marrow transplantation (alloBMT), which is associated with an immune-mediated graft-versus-leukemia (GVL) effect. Unfortunately, conditioning regimen toxicity, graft-versus-host disease (GVHD), and relapse are significant causes of treatment failure. Non- myeloablative alloBMT (NM alloBMT) is a new therapy that reduces conditioning regimen intensity and toxicity and serves as a platform for inducing GVL effects with donor lymphocyte infusions (DLI). The central hypothesis of this proposal is that the antitumor efficacy of NM alloBMT can be augmented by post-transplant administration of tumor cell-based vaccines +/- DLI, thereby circumventing the dysfunction of endogenous T cells that is frequently seen in cancer patients. Accordingly, the specific aims are to: 1) Examine the e f f e cts of donor/recipient histoincompatibility, conditioning regimen intensity, and timing of DLI on the immune response to tumor vaccines after bone marrow allografting. 2) Characterize the effects of tumor vaccine administration on GVHD and antitumor efficacy of DLI after NM alloBMT. 3) Characterize the effects of GVHD and tumor vaccines on the in vivo proliferation, cytokine production, and antitumor efficacy of transgenic T cells specific for a defined tumor antigen. My immediate and long-term goals are to translate laboratory research on tumor vaccines and alloBMT into improved therapies of cancer in the clinic. My mentors are Drs. Ephraim Fuchs and Drew Pardoll, who have expertise in translational immunology research and will support my efforts to achieve independent investigator status. All cancer immunology research at Johns Hopkins is conducted on the fourth floor of the new Bunting-Blaustein Cancer Research Building, which provides state-of-the-art equipment and a fertile intellectual environment. The Johns Hopkins Oncology Center has several clinical trials of tumor vaccines in both solid and hematologic malignancies, and performs over 200 bone marrow transplants per year, approximately half of which employ allogeneic donors.