Clinical trials of viral therapy for malignant gliomas

Abstract

Despite recent scientific advances in the understanding of the biology of malignant gliomas, there has been little change in the overall survival for this devastating disease. New and innovative treatments are under constant investigation. Starting in the 1990s, there was an interest in using viral therapeutics for the treatment of malignant gliomas. Multiple strategies were pursued, including oncolytic viral therapy, enzyme/pro-drug combinations and gene transfer with viral vectors. Multiple Phase I and II trials demonstrated the safety of these techniques, but clinically showed limited efficacy. However, this led to a better understanding of the pitfalls of viral therapy and encouraged the development of new approaches and improved delivery methods. Here we review the prior and ongoing clinical trials of viral therapy for gliomas, and discuss how novel strategies are currently being utilized in clinical trials.

Keywords::

• clinical trial
• glioblastoma
• immunotherapy
• malignant glioma
• oncolytic virus
• pro-drug
• viral therapy

Financial & competing interests disclosure

Drs. Kesari and Piccioni are co-investigators on the 2 Tocagen clinical trials mentioned in this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Initial strategies for viral therapy

• • Primary approaches involve oncolytic viruses or suicide/pro-drug therapy.

• • Initial clinical trials of viral gene therapy demonstrated good safety profiles.

• • Initial trials largely showed disappointing results in terms of response and survival.

• • Poor viral infection rates and poor tissue distribution may have limited efficacy in early trials.

• New approaches to viral therapy

• • New techniques such as MR guided biopsy, and convection enhanced delivery are being used to improve distribution and delivery.

• Oncolytic viruses

• • New oncolytic viruses, such as measles virus (MV), polio vaccine virus and parvovirus are currently in clinical trials.

• • MV and delta-24-RGD have activity against brain tumor stem cell involved in chemoradiation resistance and tumor recurrence.

• • PV crosses the blood brain barrier and may be administered IV.

• • PVS, MV and delta-24-RGD have increased targeting to glioma cells by targeting additional cell surface receptors.

• Pro-drug therapy

• • Adenovirus-tk (AV-tk) therapy is currently in upfront clinical trials with radiation and chemotherapy.

• • Toca 511 uses a nonlytic replicating retroviral vector for long-term viral production and infection of tumor cells.

• • Toca 511 combines an optimized cytosine deaminase with 5-flucytosine as an enzyme/pro-drug strategy.

• Combined therapeutics

• • Combined therapy with oncolytic AV-tk and AV-Fms-like tyrosine kinase 3 ligand leads to improved oncolysis by stimulation of the immune system and recruitment of dendritic cells.

• • Combined oncolytic AV-tk with upfront radiation and chemotherapy leads to an improved anti-tumor immune response.