UPCC#5597:A PHASE I TRIAL OF EL/E4 DELETED AD.RSVTK VIRUS W/ GANCICLOVIR

恶性胸膜间皮瘤是一种目前尚无有效治疗方法的肿瘤。我们完成了一项I期临床试验，包括胸腔内注射含有HSVtk基因的E1/E3缺失的腺病毒(Ad)(H5.010RSVtk)，然后用更昔洛韦(GCV)系统治疗26例MPM患者。剂量水平高达5x1013病毒颗粒的治疗显示出剂量依赖的、但表面上的肿瘤内tk基因转移的证据，以及对Ad载体和tk蛋白的显著免疫反应。毒性最小，没有建立H5.010RSVtk的最大耐受量(MTD)。为了改善肿瘤内的基因转移，我们已经启动了一项新的I期试验，使用了一种删除了E1/E4的“第三代”腺病毒载体(H5.001RSV.tk)，该载体在动物模型中同样有效，但免疫原性和肝脏毒性较低。这种新载体的生产成本也更低，因为同源重组的发生率更低。到目前为止，我们已经治疗了四名携带E1/E4缺失腺病毒的患者，其中两名患者的病毒颗粒分别为1.5x1013和5x1013。4例患者均通过免疫组织化学方法检测到瘤内基因转移。毒性仅限于载体滴注后的一过性发热和转氨酶的轻微升高。我们计划继续剂量递增方案，直到MTD建立为止。对载体和转基因的免疫反应的确定正在进行中，使用胸部CT和18-FDG PET成像评估肿瘤反应也在进行中。综上所述，携带E1/E4缺失载体的Ad.HSVtk/GCV基因治疗对剂量为5x1013病毒颗粒的MPM患者是安全的，有证据表明tk基因以剂量依赖的方式转移。这项临床试验得到了NIH PO1CA66726的支持。

Malignant pleural mesothelioma (MPM) is a neoplasm for which no effective therapy currently exists. We completed a Phase I clinical trial involving intrapleural delivery of an E1/E3-deleted adenovirus (Ad) containing the HSVtk gene (H5.010RSVtk), followed by systemic treatment with ganciclovir (GCV) in 26 patients with MPM. Treatment at dose levels up to 5x1013 viral particles revealed evidence of dose-dependent, but superficial, intratumoral tk gene transfer, as well as significant immune responses to the Ad vector and the tk protein. Minimal toxicities were seen and no maximally tolerated dose (MTD) of H5.010RSVtk was established. In order to improve intratumoral gene transfer, we have initiated a new Phase I trial using a "third generation" E1/E4-deleted adenoviral vector (H5.001RSV.tk) that, in animal models, is equally effective, but less immunogenic and hepatotoxic. This new vector is also more cost-efficient to produce because of a lower incidence of homologous recombination. We have treated four patients with the E1/E4-deleted adenovirus to date, two each at 1.5x1013 and 5x1013 viral particles. Intratumoral gene transfer has been detected via immunohistochemistry in all 4 patients. Toxicities have been limited to transitory pyrexia after vector instillation and minimal elevation of transaminases. We plan to continue the dose-escalation protocol until a MTD is established. Determination of the immune response to vector and transgene is ongoing, as is evaluation of tumor response using volumetric Chest CT and 18-FDG PET imaging. In summary, Ad.HSVtk /GCV gene therapy with the E1/E4-deleted vector is safe in MPM patients to doses of 5x1013 viral particles, with evidence of tk gene transfer in a dose-dependent fashion. The clinical trial is supported by NIH PO1CA66726.