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

恶性胸膜间皮瘤（MPM）是一种肿瘤，目前还没有有效的治疗方法。 我们完成了一项I期临床试验，涉及胸膜内递送含有HSVtk基因（H5.010RSVtk）的E1/E3缺失腺病毒（Ad），随后在26例MPM患者中进行更昔洛韦（GCV）全身治疗。 在高达5x 1013个病毒颗粒的剂量水平下的治疗揭示了剂量依赖性但表面的肿瘤内tk基因转移的证据，以及对Ad载体和tk蛋白的显著免疫应答。 观察到最小的毒性，并且没有确定H5.010RSVtk的最大耐受剂量（MTD）。 为了改善肿瘤内基因转移，我们已经开始了一项新的I期试验，使用“第三代”E1/E4缺失的腺病毒载体（H5.001RSV.tk），在动物模型中同样有效，但免疫原性和肝毒性较低。 由于同源重组的发生率较低，这种新载体的生产也更具成本效益。 迄今为止，我们已经用E1/E4缺失腺病毒治疗了4名患者，其中2名患者的病毒颗粒分别为1.5x1013和5x 1013。 在所有4例患者中，通过免疫组织化学检测到肿瘤内基因转移。 毒性仅限于载体滴注后的一过性发热和转氨酶的极轻微升高。 我们计划继续剂量递增方案，直至确定MTD。 对载体和转基因的免疫应答的测定正在进行中，使用体积胸部CT和18-FDG PET成像评价肿瘤应答也在进行中。 总之，使用E1/E4缺失载体的Ad.HSVtk /GCV基因治疗在MPM患者中对于5x 1013病毒颗粒的剂量是安全的，有证据表明tk基因以剂量依赖性方式转移。 该临床试验得到了NIH PO 1CA 66726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.