HIGH DOSE CHEMO & STEM CELL TRANSPLANT IN HIV NON HODGKINS LYMPHOMA

这是一项I期研究，旨在评估基因工程自体CD34外周血祖细胞(PBPC)在接受非霍奇金淋巴瘤(NHL)治疗的HIV+患者中的安全性、植入率和相对存活率。患有艾滋病和非霍奇金淋巴瘤的成年受试者，如果他们对化疗有初步反应，CD4计数为3100/毫升，并且没有活动性机会性感染，就有资格参加这项研究。在最初的化疗后，受试者将接受自体PBPC移植。通过细胞因子G-CSF动员和分离，可从外周血中浓缩PBPC。在移植前，三分之二的分离产品将被选为PBPC，分成两种培养物，并在含有细胞因子IL-3、IL-6和SCF的生长介质中生长三天。在此期间，一种培养物将用含有抗HIV双核酶基因的逆转录病毒载体转导，该逆转录病毒载体指向HIV的Tat和rev区域，而第二种培养物将用不编码核酶的对照载体转导。这两种培养的工程细胞将混合并注入受试者体内。然后，未转导的干细胞将被注入。输液后，分别于+1天、1、3、6、9、12、18、24个月采血，1、3、6、12、24个月采骨髓。与含有中性标记基因的细胞相比，含有抗HIV-1核酶基因的细胞的频率相对增加，这意味着抗HIV-1核酶赋予了细胞选择性生存优势。本研究的具体目的是：1)评价用编码抗HIV双核酶的逆转录病毒载体转导的PBPC用于接受强化化疗和干细胞移植治疗NHL的HIV阳性患者的安全性和可行性。2)确定这些基因修饰的PBPC是否能够在移植受体的血液中植入、分化和循环。3)检测外周转导核酶载体的PBPC子代细胞与对照载体标记细胞的比较存活率。4)评价大剂量化疗联合干细胞移植治疗HIV阳性非霍奇金淋巴瘤的毒性和无瘤生存期。

This is a phase I study to evaluate the safety, engraftment and relative survival of genetically engineered autologous CD34 peripheral blood progenitor cells (PBPC) in HIV+ persons undergoing therapy for non-Hodgkin's lymphoma (NHL). Adult subjects with AIDS and NHL will be eligible for this study if they had an initial response to chemotherapy and have CD4 counts 3 100/ml and are free of active opportunistic infections. After initial chemotherapy, subjects will undergo autologous PBPC transplantation. PBPC will be enriched from peripheral blood by mobilization with the cytokine G-CSF followed by apheresis. Prior to transplantation, two thirds of the apheresis product will be selected for PBPC, divided into two cultures, and grown on autologous stromal cultures for three days in growth medium containing the cytokines IL-3, IL-6, and SCF. During this time one culture will be transduced with a retroviral vector containing the anti-HIV double-ribozyme genes, which is directed toward the HIV tat and rev regions and the second culture will be transduced with a control vector that does not encode for a ribozyme. The two cultures of engineered cells will be mixed and infused into the subject. The untransduced stem cells will then be infused. Following infusions, the ratios of blood samples obtained at day +1 and months 1, 3, 6, 9, 12,18, and 24 and from marrow samples obtained at 1, 3, 6, 12, and 24 months. A relative increase in the frequency of cells containing the anti-HIV-1 TR/TAT ribozyme gene, compared to cells with the neutral marker gene, would imply that a selective survival advantage has been conferred to the cells by the anti-HIV-1 ribozymes. The specific aims of the study are: 1) to assess the safety and feasibility of administering PBPC transduced with retroviral vectors encoding an anti-HIV double ribozyme to HIV+ subjects undergoing intensive chemotherapy and stem cell transplantation for NHL. 2) To determine whether these genetically modified PBPC can engraft, differentiate, and circulate in the blood of transplanted recipients. 3) To determine the comparative survival of ribozyme-vector transduced PBPC progeny cells versus control vector marked cells in the periphery. 4) To evaluate the toxicity and disease-free survival of high dose chemotherapy with stem cell transplantation in HIV+ subjects with NHL.