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Experimental Therapeutics |
24RGD in the Treatment of Malignant Gliomas and Its Enhanced Effect with Radiotherapy1
Department of Neurosurgery [M. L. M. L., C. M. F. D., W. P. V.], Division of Gene Therapy/Department Medical Oncology [M. L. M. L., V. W. v. B., H. M. P., W. R. G.], and Department of Radiotherapy [J. v. d. B.], VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Pediatric Oncology and Pharmacology of New Drugs in Oncology, 94205 Gustave Roussy Institute, (UPRES-EA) Villejuif, France [J. G., B. G., G. V.]; Gene Therapy Center, University of Alabama, Birmingham, Alabama 35294 [R. A., D. T. C.]; and Department of Neuro-Oncology M. D. Anderson Cancer Center, Houston, Texas 77030 [J. F.]
The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. Ad
24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of Ad24 was expanded toward 
v integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-24RGD). We show that Ad5-24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 107 plaque-forming units Ad5-24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-24RGD infection decreased viability of glioma cells more effectively than Ad5-24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 106 plaque-forming units Ad5-24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-24RGD in combination with radiation therapy for treatment of these highly malignant tumors.
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