A pilot study of systemic corticosteroid administration in conjunction with intrapleural adenoviral vector administration in patients with malignant pleural mesothelioma

One of the primary limitations of adenoviral (Ad)-mediatcd gene therapy is the generation of anti-Ad inflammatory responses that fan induce clinical t oxicity and impair gene transfer efficacy. The effects of immunosuppression on these inflammatory responses, transgene expression, and toxicity have n ot yet been systematically examined in humans undergoing Ad-based gene ther apy trials. We therefore conducted a pilot study investigating the use of s ystemic corticosteroids to mitigate antivector immune responses. In a previ ous phase I clinical trial, we demonstrated that Ad-mediated intrapleural d elivery of the herpes simplex virus thymidine kinase gene (HSVtk) to patien ts with mesothelioma resulted in significant, but relatively superficial, H SVtk gene transfer and marked anti-Ad humoral and cellular immune responses .(1,2) When a similar group of patients was treated with Ad.HSVtk and a bri ef course of corticosteroids, decreased clinical inflammatory responses wer e seen, but there was no demonstrable inhibition of anti - Ad antibody prod uction or Ad-induced peripheral blood mononuclear cell activation. Corticos teroid administration also had no apparent effect on the presence of intrat umoral gene transfer. Although limited by the small numbers of patients stu died, our data suggest that systemic administration of steroids in the cont ext of Ad-based gene delivery may limit acute clinical toxicity, but may no t inhibit cellular and humoral responses to Ad vectors.