Adenovirus/Herpes Simplex-Thymidine Kinase/Ganciclovir Complex: Preliminary Results of a Phase I trial in Patients with Recurrent Malignant Gliomas

Abstract

The management of patients with glioblastoma remains challenging with an average survival of 32-56 weeks. We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry criteria for this study included: recurrent malignant glioma after surgical resection and conventional radiation therapy. At the time of recurrence, computerized volumetric resection of the tumor was performed and the ADV/HSV-tk complex was injected in the tumor bed. GC was administered 24 h after surgery (10 mg/kg/day) for 7 days. Patients were divided into 3 ADV/HSV-tk dose-escalating cohorts. Adenoviral vector shedding, and local or systemic toxicity did not occur in this study. Magnetic resonance imaging showed lack of increased brain edema in the treated patients. Histological examination of the 5 patients that had repeated surgery after gene therapy treatment showed lack of tissue toxicity. Additionally, PCR for HSV-tk was negative in the brain 3 months after injection. The patients' Karnofsky score was maintained > or = 70 in 8/10 patients (80%) and 5/9 patients (55%) 3 and 6 months respectively, after gene therapy. Ten of 11 patients survived > or = 52 weeks from diagnosis with an average survival of 112.3 weeks. One patient is still alive 248 weeks from diagnosis. These data show that the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is currently in progress.

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

“…Several vector systems have been used to deliver HSV-TK in combination with GCV, but human clinical trials have failed to provide effective treatment using tk-activated GCV as the sole therapy. [7][8][9] The bystander effect is improved by coexpression of connexin 43 (Cx43) and HSV-TK, [10][11][12] and we have confirmed these findings using our platform vector further engineered to express Cx43 in animal models of glioblastoma in vivo. 13,14 Gamma-knife radiosurgery (GKR) allows precise delivery of a single high dose of radiation to brain tumors without opening the skull.…”

Innovative Surgical Management of Glioma

“…Retroviruses, adenovirus, and herpes simplex virus-1 (HSV-1) are all currently undergoing trials as vectors for viral brain tumor therapy Replication competent retroviruses have been shown to have infection rates of 97% with specificity for tumor cells without significant effects on non-tumor cells 56 . Adenovirus and HSV-1 are used in both replication competent and replication defective forms and have shown high transgenic capacity and persistent gene expression 57 .…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…Ten of 11 treated patients survived X52 weeks from initial diagnosis with an average survival of 112.3 weeks and one patient surviving over 248 weeks from diagnosis. 65 In a phase I-II trial, both retroviruspackaging cells (PA317/tk) (eight tumors in seven patients) and adenoviruses (Adv/tk) (seven tumors in seven patients) were used for local gene therapy of recurrent malignant glioma. Seven patients received only surgery (controls).…”