SPECIFIC ADOPTIVE IMMUNOTHERAPY OF VIRAL DISEASES

自上次竞争更新以来进行的研究表明 论证了追求抗原特异性T细胞的可行性 治疗人类疾病的疗法。方法被开发出来用于 CD_4~+和CD_8~+T细胞的分离和体外高效扩增 保留正常功能的克隆，并且在I阶段试验中； 大量克隆的CD8+T细胞过继转移 巨细胞病毒被证明是无毒的，并能修复缺陷。 免疫缺陷骨髓中CD8+T细胞对巨细胞病毒的应答 移植(BMT)接受者。没有恢复CD8+T细胞的患者 免疫后出现CMV病毒血症或疾病。在这个项目中，我们 建议使用这种T细胞培养技术来确定是否采用 转移CMV特异性T细胞克隆可预防早期和晚期CMV 骨髓移植受者感染，并避免与药物相关的毒性 心理治疗。 已经发现了几种人类肿瘤，它们可能表达 免疫原性蛋白。这些疾病包括病毒相关的恶性肿瘤， 这为免疫治疗提供了有吸引力的靶点，因为 病毒蛋白代表肿瘤特异性抗原。一小部分患者 在霍奇金氏病患者体内表达几种EBV潜伏蛋白 肿瘤细胞，并提出了治疗这种人类恶性肿瘤的研究 用EBV特异性T细胞克隆。 具体目标是：1)进行收养的第二阶段研究 巨细胞病毒特异性T细胞克隆预防巨细胞病毒的免疫治疗 人类白细胞抗原相合家系异基因骨髓移植受者的疾病 成员--这项研究将包括溶细胞性CD8+和 助手CD4=T细胞克隆，并将检查治疗效果， 免疫重建，并减少频率 中性粒细胞减少，与更昔洛韦预防有关的毒性；2) 开展巨细胞病毒特异性过继免疫治疗的II期研究 用于预防晚期CMV病的T细胞克隆(+100天后) 无血缘关系的人类白细胞抗原相合的异基因骨髓移植受者 捐赠者--该研究将评估长期的治疗效果 免疫重建和产生T细胞的可行性 来自无关捐赠者的治疗；以及3)评估可行性 治疗何杰金氏病患者的安全性和潜在疗效 CD8+T细胞克隆反应性过继转移治疗EB病毒阳性肿瘤 与EB病毒编码的LMP1或LMP2蛋白在芦苇中表达- Sternberg细胞--这项初步研究将检验安全性、持久性、 转移的CD8+克隆在肿瘤部位的定位和潜能 自体或异基因骨髓移植患者的抗肿瘤活性 治疗复发/耐药霍奇金氏病。

Studies performed since the last competitive renewal have demonstrated the feasibility of pursuing antigen-specific T cell therapy for treatment of human disease. Methods were developed for isolating and efficiently expanding in vitro CD4+ and CD8+ T cells clones with retention of normal function, and, in a Phase I trail; the adoptive transfer of large numbers of cloned CD8+ T cells specific for CMV was demonstrated to be non-toxic and to reconstitute deficient CD8+ T cell responses to CMV in immunodeficient bone marrow transplant (BMT) recipients. No patient with restored CD8+ T cell immunity developed CMV viremia or disease. In this project, we propose to use this T cell culture technology to determine if adoptive transfer of CMV-specific T cell clones can prevent early and late CMV infection in BMT recipients, and avoids toxicities associated with drug therapy. Several human tumors have been identified that express potentially immunogenic proteins. These include virus-associated malignancies, which provide attractive targets for immunologic therapies, since the viral proteins represent tumor-specific antigens. A subset of patients with Hodgkin's disease express several EBV latent proteins in their tumor cells, and studies are proposed to treat this human malignancy with EBV-specific T cell clones. The specific aims are: 1) to perform a Phase II study of adoptive immunotherapy with CMV-specific T cell clones as prophylaxis for CMV disease in recipients of allogeneic BMT from HLA-matched family members -- the study will include transfer of both cytolytic CD8+ and helper CD4= T cell clones and will examine therapeutic efficacy, immunologic reconstitution, and reduction in the frequency of neutropenia, a toxicity associated with ganciclovir prophylaxis; 2) to perform a Phase II study of adoptive immunotherapy with CMV-specific T cell clones for prevention of late CMV disease (> day + 100 post- BMT) in recipients of allogeneic BMT from HLA-matched unrelated donors--the study will evaluate therapeutic efficacy, long-term immunologic reconstitution, and the feasibility of generating T cells for therapy from unrelated donors; and 3) to evaluate the feasibility safety, and potential efficacy of treating Hodgkin's disease patients with EBV+ tumors by adoptive transfer of CD8+ T cell clones reactive with the EBV-encoded LMP1 or LMP2 proteins expressed in Reed- Sternberg cells -- this pilot study will examine safety, persistence, localization of transferred CD8+ clones to sites of tumor, and potential antitumor activity in patients undergoing autologous or allogeneic BMT for relapsed/resistant Hodgkins' disease.