Sterman D H, Molnar-Kimber K, Iyengar T, Chang M, Lanuti M, Amin K M, Pierce B K, Kang E, Treat J, Recio A, Litzky L, Wilson J M, Kaiser L R, Albelda S M
Division of Pulmonary and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Cancer Gene Ther. 2000 Dec;7(12):1511-8. doi: 10.1038/sj.cgt.7700269.
One of the primary limitations of adenoviral (Ad) -mediated gene therapy is the generation of anti-Ad inflammatory responses that can induce clinical toxicity and impair gene transfer efficacy. The effects of immunosuppression on these inflammatory responses, transgene expression, and toxicity have not yet been systematically examined in humans undergoing Ad-based gene therapy trials. We therefore conducted a pilot study investigating the use of systemic corticosteroids to mitigate antivector immune responses. In a previous phase I clinical trial, we demonstrated that Ad-mediated intrapleural delivery of the herpes simplex virus thymidine kinase gene (HSVtk) to patients with mesothelioma resulted in significant, but relatively superficial, HSVtk gene transfer and marked anti-Ad humoral and cellular immune responses. When a similar group of patients was treated with Ad.HSVtk and a brief course of corticosteroids, decreased clinical inflammatory responses were seen, but there was no demonstrable inhibition of anti -Ad antibody production or Ad-induced peripheral blood mononuclear cell activation. Corticosteroid administration also had no apparent effect on the presence of intratumoral gene transfer. Although limited by the small numbers of patients studied, our data suggest that systemic administration of steroids in the context of Ad-based gene delivery may limit acute clinical toxicity, but may not inhibit cellular and humoral responses to Ad vectors.
腺病毒（Ad）介导的基因治疗的主要局限性之一是产生抗Ad炎症反应，这种反应可诱发临床毒性并损害基因转移效率。在接受基于Ad的基因治疗试验的人类中，免疫抑制对这些炎症反应、转基因表达和毒性的影响尚未得到系统研究。因此，我们开展了一项初步研究，调查全身使用皮质类固醇以减轻抗载体免疫反应的情况。在之前的一项I期临床试验中，我们证明将腺病毒介导的单纯疱疹病毒胸苷激酶基因（HSVtk）经胸膜内递送至间皮瘤患者体内，可实现显著但相对表浅的HSVtk基因转移，并引发明显的抗Ad体液免疫和细胞免疫反应。当对一组类似患者使用Ad.HSVtk并给予短期皮质类固醇治疗时，临床炎症反应有所减轻，但抗Ad抗体产生或Ad诱导的外周血单个核细胞激活未得到明显抑制。皮质类固醇给药对肿瘤内基因转移的存在也没有明显影响。尽管本研究受限于研究的患者数量较少，但我们的数据表明，在基于Ad的基因递送过程中全身给予类固醇可能会限制急性临床毒性，但可能无法抑制对Ad载体的细胞免疫和体液免疫反应。
