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

R-EPOCH 后的干细胞基因治疗艾滋病患者非霍奇金淋巴瘤

• 批准号: 8805835
• 负责人: John A Zaia
• 金额: $ 49.63万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805835
• 关键词: AIDS population; AIDS-Related Lymphoma; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Autologous; Behavior Therapy; CCR5 gene; CD4 Positive T Lymphocytes; Catalytic RNA; Cell Therapy; Cells; Cities; Clinical; Clinical Protocols; Cyclophosphamide; Data; Elements; Engraftment; Enrollment; Etoposide; Exons; Gene Transfer; Gene-Modified; Genes; Genetic; Goals; HIV; HIV Infections; HIV-1; Health; Hematopoietic; Immune system; In complete remission; Interruption; Lentivirus Vector; Lymphoma; Malignant Neoplasms; Methods; Myeloablative Chemotherapy; Non-Hodgkin' s Lymphoma; Outcome; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Population; Prednisone; Procedures; RNA; RNA Interference; Relapse; Research; Resistance; Safety; Salvage Therapy; Serious Adverse Event; Stem cell transplant; Stem cells; Subfamily lentivirinae; Subgroup; Testing; Therapeutic; Transplantation; United States National Institutes of Health; Vincristine; Viral; Work; antiretroviral therapy; base; chemokine receptor; chemotherapy; combat; conditioning; experience; gene therapy; improved; inhibitor/antagonist; pressure; rituximab; small hairpin RNA; stem

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.

描述（由申请人提供）：HIV 相关淋巴瘤继续使 HIV/AIDS 的长期管理变得复杂化，并且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，NIH 临床中心的工作表明，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%。这些患者中艾滋病毒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) 清髓挽救治疗的 ARL 患者可以安全地接受抗 HIV 基因治疗，并长期植入基因标记的 PBMC。该应用将测试接受与 R-EPOCH 相关的降低强度调理治疗的 ARL 患者是否可以植入类似的基因修饰自体 HSPC。如果是这样，艾滋病毒感染本身可能会选择具有耐药性的后代细胞。因此，拟议的临床方案将在成功完成 R-EPOCH 后，使用编码三种有效 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rHIV7-shI-TAR-CCR5RZ]编码3种形式的抗HIV RNA：针对HIV-1 tat/rev (shI)中的外显子的短发夹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 临床中心入组并接受治疗，细胞产品制造和遗传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，并且该手术是安全的。第二个假设是，转基因后代 CD4 细胞将受到保护，免受 HIV 侵害，并在 ATI 期间在选择性病毒压力下扩增。