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: 8639234
• 负责人: John A Zaia
• 金额: $ 46.56万
• 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/8639234
• 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; 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; public health relevance; 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(申请人提供)：艾滋病毒相关淋巴瘤继续使艾滋病毒/艾滋病的长期治疗复杂化，随着抗逆转录病毒疗法(ART)的改善，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、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，完全缓解率为73-91%。在这些患者中，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应用的潜力。在这方面，来自希望之城的研究表明，失败的一线治疗失败的ARL患者需要使用自体外周造血干细胞和祖细胞移植(HCT)进行清髓挽救治疗，可以通过长期植入基因标记的PBMC来安全地接受抗HIV基因治疗。这项应用将测试ARL患者接受与R-EPOCH相关的降低强度条件化治疗是否可以植入类似的基因修饰的自体HSPC。如果是这样的话，艾滋病毒感染本身就有可能选择具有抵抗力的后代细胞。因此，建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中断期间观察(ATI)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-1TAT/REV(SHI)外显子的RNAi，针对HIV TAT反应元件(TAR)的诱饵，以及靶向宿主细胞CCR5趋化因子受体(CCR5RZ)的核酶。患者将在NIH临床中心接受登记和治疗，细胞产品制造和遗传结果将在希望之城进行。假说：最初的假说是，将经rHIV7-SHI-TAR-CCR5RZ治疗的自体HSPC移植到经过R-EEDCH治疗的ARL患者体内是可行的，而且这一过程是安全的。第二种假设是，转基因的后代CD4细胞将受到保护，不受艾滋病毒的影响，并在ATI期间在选择性病毒压力下扩张。