Bacteriophage-guided gene therapy with chemotherapy holds promise in treating glioblastomaPublished: March 1, 2019
Researchers at Imperial College London demonstrate the potential of using a combination therapy strategy, chemovirotherapy to treat glioblastomas.
Glioblastomas are the most aggressive tumors of the central nervous system, and the least responsive to intervention. Chemotherapy using temozolomide (TMZ) is a widely used option for GBM patients, but the therapy has limited efficacy. Therefore, novel therapeutic approaches are urgently needed to effectively treat GBM.
In the present study published in EMBO Molecular Medicine, Dr Amin Hajitou and team at Imperial’s Phage Therapy Group combined TMZ chemotherapy with bacteriophage-mediated gene therapy and evaluated its effect on GBM.
M13 bacteriophage, a virus that infects only bacterial cells was used in the study. An engineered version of this bacteriophage vector was then created. The resulting hybrid vector contained a phage capsid with recombinant AAV genomes (AAV vector encoding HSVtk under a tumor‐specific Grp78 promoter) incorporated into it. In addition, the phage capsid also displayed RGD4C, a ligand known to bind αvβ3 integrin cell surface receptors overexpressed on GBM.
The team investigated the effects of combining TMZ chemotherapy and targeted gene therapy, termed chemovirotherapy, against intracranial models of human glioblastoma.
Following intravenous administration in mice, the hybrid phage vector delivered the therapeutic AAV genome into GBM to generate expression of the HSVtk. HSVtk resulted in phosphorylation of ganciclovir within GBM and subsequent tumor destruction by apoptosis. Similar results were obtained when TMZ was administered. It induced the Grp78 promoter activity resulting in the expression of the HSVtk and subsequent phosphorylation of ganciclovir.
Combining phage gene therapy with TMZ resulted in further regression of tumors. The effect was synergistic and more pronounced than gene therapy or chemotherapy alone.
Given the acceptability of TMZ for human therapy against glioblastoma and the safety of bacteriophage in humans, results from this study highlight the translational potential of this combination therapy to treat glioblastoma.
Source: Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma. Przystal JM et al., EMBO Molecular Medicine February 2019. DOI