Glioma virus therapies between bench and bedside

Abstract

Despite extensive research, current glioma therapies are still unsatisfactory, and novel approaches are pressingly needed. In recent years, both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment, and the mechanistic background of their cytotoxicity has been unveiled. A growing number of clinical trials have convincingly established viral therapies to be safe in glioma patients, and maximum tolerated doses have generally not been reached. However, evidence for therapeutic benefit has been limited: new generations of therapeutic vectors need to be developed in order to target not only tumor cells but also the complex surrounding microenvironment. Such therapies could also direct long-lasting immune responses toward the tumor while reducing early antiviral reactions. Furthermore, viral delivery methods are to be improved and viral spread within the tumor will have to be enhanced. Here, we will review the outcome of completed glioma virus therapy trials as well as highlight the ongoing clinical activities. On this basis, we will give an overview of the numerous strategies to enhance therapeutic efficacy of new-generation viruses and novel treatment regimens. Finally, we will conclude with approaches that may be crucial to the development of successful glioma therapies in the future.

Keywords: gene therapy; glioblastoma; oncolysis.

Fig. 1.

Strategies to improve efficacy of virus therapies. Several clinical trials have been performed using therapeutic viruses to treat gliomas. Although well tolerated overall, there is a need for more efficacious viruses, and ongoing bench research is exploring several areas of possible improvement. (A) Intratumoral application of therapeutic viruses may be performed using convection-enhanced delivery. Alternatively, viruses may be administered intravenously, but there is a need for shielding them from host serum factors using chemicals, a chimeric design, or carrier cells, which may also facilitate targeted delivery toward the tumor tissue. (B) Specificity is enhanced during viral entry, allowing the virus to enter tumor cells only by modification of the attachment-mediating surface proteins employing targeting peptides, antibodies and their derivatives, or chimeric capsids/envelopes. Furthermore, specificity can be achieved at a post-entry level with viral replication restricted to target cells utilizing glioma-specific promoters, differentially expressed microRNAs (miRNA), or the deletion of essential viral genes whose function is complemented in tumor cells. Both concepts can be applied to target both tumor bulk and tumor stem cells. (C) When viral genes are engineered to be regulated by hypoxia-responsive promoters, viral replication can be enhanced in areas of low oxygenation, a typical glioma phenotype. (D) If the therapeutic virus does not possess intrinsic properties facilitating intratumoral dissemination like syncytia formation, intratumoral spread can be enhanced by encoding enzymes capable of degrading the tumor's extracellular matrix (ECM) or by combination treatments with drugs that modulate the composition of the tumor stroma or vascular permeability. (E) The immune system plays a complex role during viral therapy of gliomas. Especially in the early phases of treatment, antiviral effects of the innate immune system and preexisting neutralizing factors need to be suppressed by pharmacological intervention. (F) A beneficial adaptive immune response directed against the tumor can be elicited by encoding immunostimulatory transgenes and/or tumor-associated antigens (TAAs).