Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with recurrent malignant brain tumors

Between December 1996 and September 1998, 13 patients with advanced recurre nt malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarco ma, and 3 with anaplastic astrocytoma) were treated with a single intratumo ral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector pa rticles (VP) of a replication-defective adenoviral vector bearing the herpe s simplex virus thymidine kinase gene driven by the Rous sarcoma virus prom oter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infect ious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses less than or equal to2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with t he highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity w ith confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succu mbing to tumor progression. Ten patients died within 10 months of treatment , 9 from tumor progression and 1 with sepsis and endocarditis. Neuropatholo gic examination of postmortem tissue demonstrated cavitation at the injecti on site, intratumoral foci of coagulative necrosis, and variable infiltrati on of the residual tumor with macrophages and lymphocytes.