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）的改进，ARL的一线化疗取得了极好的结果。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、强的松、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%。在这些患者中，HIV感染的管理问题仍然存在，这表明基因转移在这一人群中的应用潜力。City of Hope的研究表明，在一线治疗失败并需要自体外周血干细胞（HSPC）移植（HCT）进行清髓挽救治疗的ARL患者可以安全地接受长期植入基因标记的PBMC的抗hiv基因治疗。该应用将测试接受R-EPOCH相关的低强度调节治疗的ARL患者是否可以移植类似基因修饰的自体HSPC。如果是这样，HIV感染本身可能会选择具有抗性的后代细胞。因此，拟议的临床方案将治疗HIV感染的AR患者，在R-EPOCH成功完成后，用慢病毒修饰的自体HSPC编码三种有效的HIV抑制剂，并在ART中断（ATI）期间观察对HIV感染的影响。慢病毒载体[称为rHIV7-shI-TAR-CCR5RZ]编码3种形式的抗HIV RNA：针对HIV-1 tat/rev （shI）外显子的短发夹RNA形式的RNAi， HIV tat反应元件（TAR）的诱饵，以及针对宿主细胞CCR5趋化因子受体（CCR5RZ）的核酶。患者将在NIH临床中心登记和治疗，细胞产品的制造和基因结果将在希望之城进行。假设：主要假设是，在接受R-EPOCH治疗ARL后，将自体rHIV7-shI-TAR-CCR5RZ治疗的HSPC移植到患者体内是可行的，并且该过程是安全的。第二种假设是，经过基因修饰的后代CD4细胞将免受艾滋病毒的侵害，并在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.