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Differential Effects of Combined Ad5-24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Authors' Affiliations: Departments of ¹ Neurosurgery, ² Radiotherapy, ³ Medical Oncology, and ⁴ Pathology, and ⁵ Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and ⁶ Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands

Requests for reprints: Martine L.M. Lamfers, Department of Neurosurgery, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Phone: 31-10-7048531; Fax: 31-10-4088365; E-mail: M.Lamfers{at}erasmusmc.nl.

Purpose: The integrin-targeted conditionally replicating adenovirus Ad5-24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model.

Experimental Design and Results: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-24RGD.

Conclusions: Combined treatment with Ad5-24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.