Going viral: Unraveling the immune response in oncolytic virotherapy for glioblastoma

Patients with a malignant primary brain tumor, glioblastoma, have a dismal prognosis.
Currently, the standard treatment is surgery (if possible) followed by concomitant radio- and chemotherapy. Despite increased efforts in the past years to improve survival of these patients, including numerous clinical trials testing newly developed targeted compounds, no progress has been made. Part One of this thesis is focused on the development of a new, more representative in vitro culture model for primary glioma cell cultures and it's applicability for in vitro drug screening. Part Two of this thesis is focused on oncolytic virotherapy as a promising new therapy for glioblastoma These viruses are able to replicate inside tumor cells, leaving normal cells unharmed, and inducing tumor
cell lysis. Next to this direct oncolytic effect, it is thought that OVs also have an immune
stimulatory effect by inducing an anti-tumor immune response. The second part of this
thesis is aimed at the characterization of this immune response for the oncolytic adenovirus Delta24-RGD. This thesis shows that the therapeutic efficacy of the OV is actually mediated by an induced anti-tumor immune response. Intra-tumoral administration of OVs gives massive influx of innate immune cells, e.g. macrophages, natural-killer cells and dendritic cells. So-called M2 macrophages that display a pro-tumoral phenotype are abundantly present in gliomas. OV therapy changes this phenotype to M1 macrophages, that have anti-tumoral properties. During a clinical phase 1/2 trial testing the oncolytic virus Delta24-RGD in recurrent glioblastoma patients, an immune response by the induction of cytokines and influx of immune cells is elicited. Interestingly, this response is only seen in a subset of patients, among these patients the two long-term surviving ones.