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，对26例MPM患者胸膜内注入含有HSVtk基因（H5.010RSVtk）的E1/ e3缺失腺病毒（Ad），随后用更昔洛韦（GCV）进行全身治疗。在高达5x1013个病毒颗粒的剂量水平下治疗，显示了剂量依赖的证据，但表面上，肿瘤内tk基因转移，以及对Ad载体和tk蛋白的显著免疫反应。H5.010RSVtk毒性最小，未建立最大耐受剂量（MTD）。为了改善肿瘤内基因转移，我们已经启动了一项新的I期试验，使用“第三代”E1/ e4缺失腺病毒载体（H5.001RSV.tk），在动物模型中，该载体同样有效，但免疫原性和肝毒性较小。由于同源重组的发生率较低，这种新载体的生产成本也更高。迄今为止，我们已经治疗了4例E1/ e4缺失腺病毒患者，其中2例为1.5x1013和5x1013病毒颗粒。所有4例患者均通过免疫组化检测到瘤内基因转移。毒性仅限于载体注入后的短暂发热和转氨酶的轻微升高。我们计划继续实施剂量递增方案，直到确定最高预防措施。测定对载体和转基因的免疫反应正在进行中，使用胸部容积CT和18-FDG PET成像评估肿瘤反应也在进行中。总之，Ad。在MPM患者中，使用E1/ e4缺失载体进行HSVtk /GCV基因治疗对5 × 1013剂量的病毒颗粒是安全的，有证据表明tk基因以剂量依赖的方式转移。该临床试验由NIH PO1CA66726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.