TUMOR VACCINES AFTER NON MYELOABLATIVE ALLOGRAFTING

D E S C RIPTION（申请人描述）： 多种耐药 热变形 恶性肿瘤 是 有效 处理 通过 高 剂量 化疗加放疗后异基因骨髓移植 （alloBMT），其与免疫介导的移植物抗白血病相关。 (GVL)效果 不幸的是，预处理方案毒性，移植物抗宿主 疾病（GVHD）和复发是治疗失败的重要原因。 非 清髓性alloBMT（NM alloBMT）是一种新的治疗方法， 方案强度和毒性，并作为诱导GVL的平台 供体淋巴细胞输注（DLI）。 这个问题的核心假设是 建议NM alloBMT的抗肿瘤功效可以通过以下方式增强： 移植后施用基于肿瘤细胞的疫苗+/- DLI，从而 避免了内源性T细胞的功能障碍，这种功能障碍经常在 癌症患者。 因此，具体目标是：1）审查 供体/受体组织不相容性的效应，预处理方案 DLI对肿瘤疫苗免疫应答的影响， 骨髓移植 2)描述肿瘤疫苗的作用 在NM alloBMT后，DLI对GVHD和抗肿瘤功效的影响。 第三章 表征 GVHD和肿瘤疫苗对体内 转基因T细胞的增殖、细胞因子产生和抗肿瘤功效 对确定的肿瘤抗原特异的细胞。 我的近期和长期目标是将肿瘤的实验室研究成果 疫苗和alloBMT在临床上用于改善癌症治疗。 我 导师是Ephraim Fuchs博士和Drew Pardoll博士，他们在以下方面拥有专业知识： 翻译免疫学研究，并将支持我的努力，实现 独立调查员身份。 约翰癌症免疫学研究 霍普金斯是在新的邦廷-布劳斯坦癌症四楼进行 研究大楼，提供最先进的设备和肥沃的土壤。 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恶性肿瘤中的临床试验， 每年进行超过200例骨髓移植， 他们雇佣同种异体的捐赠者。

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.