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  • Review Article
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Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress

Nature Clinical Practice Oncology volume 4, pages 101–117 (2007)Cite this article

Abstract

Therapeutic oncolytic viruses (virotherapeutics) constitute a novel class of targeted anticancer agents that have unique mechanisms of action compared with other cancer therapeutics. The development of virotherapeutics has evolved from the use of in vitro-passaged strains (first generation), to genetically engineered selectivity-enhanced viruses (second generation) and finally to genetically engineered transgene-expressing 'armed' oncolytic viruses (third generation). Descriptions of cancer remissions following virus infections date back to a century ago. Initial patient treatment publications, written up to 50 years ago, consisted of case reports or case series of treatment with first-generation, non-engineered viruses. Over the past decade, hundreds of patients with cancer have been treated on prospectively designed clinical trials (including phase III), evaluating over 10 different agents, inlcluding engineered second-generation and third-generation viruses. This Review summarizes and interprets the data from clinical reports over the last century, including safety, efficacy and biological end points (viral and immunologic). Systemic safety and efficiacy has been clearly demonstrated with some virotherapeutics. The implications of these data for future virotherapy development are discussed.

Key Points

  • Oncolytic viruses can be safely administered into patients via different routes; systemic efficacy has been demonstrated with some virotherapeutics

  • Virus replication can be demonstrated in vivo after local administration, and with some viruses after intravenous administration

  • There is no cross-resistance of oncolytic viruses with standard therapeutics; response to virotherapy is virus species and tumor-specific

  • Virotherapy enhances or synergizes with chemotherapy and radiotherapy

  • Modern technologies have allowed the incorporation of transgenes into oncolytic viruses for therapeutic or monitoring purposes

  • Neutralizing antibodies do not affect efficacy with local and local-regional administration, and the induction of immune reactions may have a role in antitumoral efficacy of viruses

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Figure 1: Schematic of oncolytic virotherapy mechanism of action: viral replication, cell killing, virus release and spread within cancer tissue but not normal tissues.
Figure 2: Timeline of the clinical history of oncolytic viruses.
Figure 3: Tumor responses following incidental viral infection, vaccination or treatment with non-engineered virus strains.
Figure 4: Complete response of recurrent glioblastoma multiforme during chronic intravenous Newcastle disease virus (HUJ strain) therapy.
Figure 5: Engineered oncolytic adenovirus designs.
Figure 6: Mathematical modeling analysis of virotherapeutic replication and shedding into the blood in patients with cancer following: (A) hepatic artery infusion of dl1520 adenovirus (ONYX-015) in patient with colorectal liver metastases; (B) intravenous infusion of CG7870 adenovirus in patients with metastatic prostate carcinoma.
Figure 7: Tumor responses following treatment with engineered viruses, with and without chemotherapy.

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Author notes

  1. E Galanis is Associate Professor of Oncology at the Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

  2. D Kirn is President and CEO of JENNEREX Biotherapeutics Inc., San Francisco, CA, USA, and a Visiting Professor at the Department of Clinical Pharmacology, University of Oxford Medical School, Oxford, UK.

Authors and Affiliations

  1. T-C Liu is a Research Fellow at the Brain Tumor Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,

    Ta-Chiang Liu, Evanthia Galanis & David Kirn

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Correspondence to David Kirn.

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Competing interests

D Kirn has declared he is has ownership in and employment by Jennerex Biotherapeutics ULC, a company developing development oncolytic viruses for cancer patients. The other authors declared they have no competing interests.

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Liu, TC., Galanis, E. & Kirn, D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Rev Clin Oncol 4, 101–117 (2007). https://doi.org/10.1038/ncponc0736

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