Clinical implications of cytomegalovirus in glioblastoma progression and therapy

Abstract

Glioblastoma (GBM) is one of the deadliest brain cancers with a median survival of only 15 months. This poor prognosis has prompted exploration of novel therapeutic targets for GBM patients. Human cytomegalovirus (HCMV) has been implicated in GBM; however, its impact remains poorly defined, and there is conflicting data over the presence of HCMV in tumors. Nonetheless, clinical trials targeting HCMV have shown promising initial data, and evidence suggests that HCMV may negatively impact GBM patient survival by multiple mechanisms including changes in GBM cell behavior and the tumor microenvironment (TME) that potentiate tumor progression as well as therapy-induced virus reactivation. Moreover, HCMV has many effects on host immunity that could impact tumor behavior by altering the TME, which are largely unexplored. The goal of this review is to describe these potential interactions between HCMV and GBM. Better understanding of these processes may allow the development of new therapeutic modalities to improve GBM patient outcomes.

Fig. 1. Association of HCMV with cancer hallmarks.

HCMV genes have been reported to induce multiple cancer hallmarks as defined by Hanahan and Weinberg^,, highlighted in blue are four emerging hallmarks.

Fig. 2. Overview of Therapeutic Strategies Targeting HCMV in GBM.

HCMV seropositivity and reactivation have been associated with negative outcomes in GBM. Several therapeutic approaches are currently in clinical trials for GBM patients including the antiviral drug valganciclovir, HCMV pp65 pulsed DC vaccine, peptide vaccine PEP-CMV and nucleic acid-based vaccine ITI-1001. Other pre-clinical approaches are also being tested using T cell based immunotherapies.

Fig. 3. Mechanisms of antiviral drugs in GBM.

Valganciclovir (VGCV) is converted to ganciclovir (GCV) by hepatic esterases then GCV is intracellularly phosphorylated by HCMV viral protein kinase pUL97 and further downstream phosphorylated by cellular kinases to produce its active form ganciclovir triphosphate, which competitively inhibits deoxyguanosine triphosphate incorporation into DNA and preferentially targets HCMV viral DNA polymerase. Brincidofovir (BCV) is a lipid conjugate of cidofovir (CDV) with improved cellular uptake. Upon cellular entry, lipases cleave the lipid chain releasing CDV which is then transformed into its active form cidofovir diphosphate by intracellular kinases. CDV is a competitive inhibitor of deoxycytosine triphosphate resulting in viral DNA chain termination.