Stem Cell Gene Therapy Following R-EPOCH for Non-Hodgkin Lymphoma in AIDS Patient

描述（由申请人提供）：HIV相关淋巴瘤继续使HIV/AIDS的长期管理复杂化，随着抗逆转录病毒治疗（ART）的改善，ARL的一线化疗结果非常好。例如，美国国立卫生研究院临床中心的研究表明，使用R-EPOCH [依托泊苷、泼尼松、长春新碱、环磷酰胺和羟基柔红霉素与利妥昔单抗同时使用]治疗ARL的完全缓解率为73- 91%。HIV感染的管理问题在这些患者中仍然存在，这表明基因转移在这一人群中的应用潜力。City of Hope在这方面的工作表明，一线治疗失败并需要自体外周造血干细胞和祖细胞[HSPC]移植（HCT）进行清髓性挽救治疗的ARL患者可以安全地接受抗HIV基因治疗，长期植入基因标记的PBMC。本申请将测试接受与R-EPOCH相关的降低强度预处理治疗的ARL患者是否可以植入类似的基因修饰的自体HSPC。如果是这样的话，HIV感染本身可能会选择抗性后代细胞。因此，拟定的临床方案将在成功完成R-EPOCH后，使用编码三种强效HIV抑制剂的慢病毒修饰的自体HSPC治疗HIV感染的AR患者，并在ART中断（ATI）期间观察对HIV感染的影响。慢病毒载体[称为rHIV 7-shI-TAR-CCR 5 RZ]编码3种形式的抗HIV RNA：靶向HIV-1达特/rev（shI）外显子的短发夹RNA形式的RNAi、HIV TAT反应元件（TAR）的诱饵和靶向宿主细胞CCR 5趋化因子受体（CCR 5 RZ）的核酶。患者将在NIH临床中心入组并接受治疗，细胞产品生产和遗传结局将在City of Hope进行。假设：主要假设是，将自体rHIV 7-shI-TAR-CCR 5 RZ治疗的HSPC移植到接受R-EPOCH治疗ARL的患者体内是可行的，并且该手术是安全的。第二个假设是，基因修饰的后代CD 4细胞将受到保护，免受HIV感染，并将在ATI期间在选择性病毒压力下扩增。

DESCRIPTION (provided by applicant): HIV associated lymphoma continues to complicate the long-term management of HIV/AIDS, and as antiretroviral therapy (ART) has improved, frontline chemotherapy for ARL results in superb outcome. Work from the NIH Clinical Center, for example, has shown that the use of R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, and hydroxydaunorubicin used concurrently with rituximab] for ARL, has a complete response rate of 73-91%. The problem of management of HIV infection continues in these patients, suggesting the potential for application of gene transfer in this population. Work from City of Hope has shown in this regard that ARL patients who fail frontline therapy and require myeloablative salvage therapy with autologous peripheral hematopoietic stem and progenitor cell [HSPC] transplantation (HCT) can safely undergo anti-HIV gene therapy with long-term engraftment of gene-marked PBMC. This application will test whether ARL patients receiving the reduced intensity conditioning therapy associated with R-EPOCH can engraft similarly gene-modified autologous HSPC. If so, it is possible that HIV infection itself could select for resistant progeny cells. Thus, the proposed clinical protocol will treat HIV-infected AR patients, following successful completion of R-EPOCH, with autologous HSPC modified with a lentivirus encoding three potent HIV inhibitors with observation during ART interruption (ATI) for effect on HIV infection. The lentivirus vector [called rHIV7-shI-TAR-CCR5RZ ] encodes 3 forms of anti-HIV RNA: RNAi in the form of a short hairpin RNA targeted to an exon in HIV-1 tat/rev (shI), a decoy for the HIV TAT-reactive element (TAR), and a ribozyme that targets the host cell CCR5 chemokine receptor (CCR5RZ). Patients will be enrolled and treated at the NIH Clinical Center and the cell product manufacture and genetic outcome will be performed at City of Hope. Hypotheses: The primary hypothesis is that it is feasible to transplant autologous rHIV7-shI-TAR-CCR5RZ- treated HSPC into patients following treatment with R-EPOCH for ARL and this the procedure is safe. A secondary hypothesis is that the genetically-modified progeny CD4 cells will be protected from HIV and will expand under selective viral pressure during ATI.