Oncolytic viruses for treatment of malignant brain tumours

Abstract

Wild type viruses have been known for decades for their capability to destroy malignant tumour cells upon infection and intracellular replication. Genetic engineering of such viruses was, however, only recently done in an attempt to improve their utility as biological anticancer agents. Wild type or recombinant viruses able to selectively destroy tumour cells while sparing normal tissue are known as oncolytic viruses. Most oncolytic viruses currently investigated in clinical trials are derived from adenovirus (AV) or herpes simplex virus type I (HSVI). More than 300 patients with solid tumours were now treated in clinical trials with oncolytic viruses, and in most cases virus was administered directly into the tumour mass. About 10% of the above patients had recurrent malignant glioma. Total intratumoral doses of up to 2 x 10(12) virus particles were well tolerated, and in general no severe side effects resulted from the clinical use of oncolytic AV and HSVI, either in the brain or in the rest of the body. Encouraging anti-tumoral activity was demonstrated in some types of tumours treated locally with oncolytic viruses, and systemic chemotherapy was found to potentiate the anti-tumour effect of virus mediated oncolysis. In malignant glioma, standard gene therapy approaches employing non-replicating virus vectors failed to demonstrate significant benefit in clinical studies. Therapy with oncolytic viruses seems to hold more promise in early clinical trials than gene therapy with non-replicating virus vectors. However, further major advancements in virus designs, application modalities, and understanding of the interactions of the host's immune system with the virus are clearly needed before oncolytic virus therapy of malignant brain tumours can be introduced to clinical practice.