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（由申请人提供）：HIV相关的淋巴瘤继续使HIV/AIDS的长期治疗复杂化，并且随着抗逆转录病毒疗法（ART）的改善，前线化学疗法可导致ARL的前线化疗。例如，来自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，环磷酰胺和羟基多糖蛋白与Rituximab同时使用的ARL]的全部应答率为73-91％。这些患者的HIV感染治疗问题仍在继续，这表明在该人群中使用基因转移的潜力。希望之城的工作在这方面表明，未通过自体外周血造血茎和祖细胞和祖细胞[HSPC]移植（HCT）的ARL患者需要骨髓性挽救疗法（HCT）可以安全地接受抗HIV基因治疗，并长期对基因标记pBMC进行长期雕刻。该应用将测试是否接受与R-Epoch相关的强度调节疗法降低的ARL患者是否可以类似地植入基因修饰的自体HSPC。如果是这样，HIV感染本身可能会选择抗性后代细胞。因此，提出的临床方案将在成功完成R-Epoch后处理HIV感染的AR患者，自体HSPC用慢跑病毒修饰，用慢跑病毒编码三种有效的HIV抑制剂，并在ART中断（ATI）中观察到对HIV感染的影响。 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).患者将在NIH临床中心接受和治疗，并且将在希望之城进行细胞产物制造和遗传结果。假设：主要的假设是，在用R-Epoch进行ARL治疗后，移植自体rhiv7-shi-shi-tar-CCR5RZ处理的HSPC是可行的，并且该程序是安全的。次要假设是，遗传改性后的后代CD4细胞将受到HIV的保护，并将在ATI期间选择性病毒压力下扩展。