How can we trick the immune system into overcoming the detrimental effects of oncolytic viral therapy to treat glioblastoma?

Although China approved the use of the H101 adenovirus for the treatment of various solid cancers in 2005, similar viruses have not obtained clinical approval in the USA [1]. While there are several Phase III trials testing the therapeutic efficacy of oncolytic viruses (OVs) in patients diagnosed with melanoma, bladder and advanced head and neck cancers (ClinicalTrials.gov identifiers: NCT01438112, NCT00769704, NCT01166542 [101]), there are currently only Phase I/II OV trials for patients with glioblastoma (GB), which highlights the difficulty associated with treating this particular disease (ClinicalTrials.gov identif iers: NCT00157703, NCT01174537, NCT00528684, NCT01301430, NCT01582516 [101]). The uniqueness of the brain tumor microenvironment – the extracellular matrix, leaky blood vessels and immune responses – has collectively been shown to limit OV delivery, replication, spread and efficacy. Of these factors, the impact of the host immune response on OV efficacy is perhaps the most complicated to understand. In the context of OV therapy, the immune response is a double-edged sword. On one hand, innate immune responses result in rapid viral clearance and decreased OV efficacy; on the other hand, immune responses elicited after viral infection also have the potential to activate an adaptive antitumor immune response to promote tumor eradication. Here, we summarize some of the challenges and recent progress made by investigators in manipulating the immune response with respect to OV therapies for GB.