Oncolytic virotherapy

Abstract

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.

Figure 1

Barriers to efficient oncolytic virus delivery via the bloodstream (virus neutralization by serum factors, sequestration by the mononuclear phagocytic system or lack of extravasation) and solutions to circumvent them.

Figure 2

Factors constraining intratumoral virus spread (host innate or acquired immunity and extracellular matrix) and solutions to circumvent them.

Figure 3. A timeline of milestones in the development of oncolytic virotherapy to improve virus specificity, potency, delivery and spread

SPECIFICITY: (1) Translational targeting: 1991, Engineering of a replication-competent HSV attenuated for neurovirulence for glioma treatment. (2) Transcriptional targeting: 1997, targeting of HSV using albumin promoter/enhancer for hepatoma cells and Ad using Prostate specific antigen (PSA) promoter for prostate cancer cells, (3) Transductional targeting: 2005, targeting entry and cytopathic effects of oncolytic measles virus by display of single-chain antibody on the virus attachment protein, (4) MicroRNA targeting: 2008, to control unwanted toxicity of picornarvirus and vesicular stomatitis virus while retaining antitumor activity, (5) DNA shuffling, 2008, Mixing a pool adenoviral serotypes and passaging the pools under conditions that invite recombination between serotypes to generate tumor selective virus. POTENCY: (1) Prodrug activation: 1998, an oncolytic adenovirus expressing cytosine deaminase and HSV-Tk designed to work in combination with 5-FC and Ganciclovir, (2) Proapoptotic genes: 2000, introduction of the adenovirus death protein (ADP) into an oncolytic adenovirus to enhance its cytotoxicity, (3) Immune stimulation: 2001, oncolytic HSV encoding IL-12 and GM-CSF to recruit T lymphocyte-mediated antitumor immune response, (4) Radioisotope: 2004, an oncolytic measles virus encoding the human sodium iodide symporter (NIS) which concentrates beta-emitting (radiovirotherapy) and gamma-emitting isotopes (imaging), (5) 2006, Matrix degrading proteins: adenovirus encoding relaxin protein to enhance virus intratumoral spread, (6) Shuffling: 2008, Mixing a pool adenoviral serotypes and passaging the pools under conditions that invite recombination between serotypes to generate more potent adenovirus ColoAd1 . DELIVERY & SPREAD: (1) Immune suppressive drugs: 1999, Addition of cyclophosphamide to combat and innate and adaptive antiviral immunity to enhance intratumoral spread of HSV, (2) Cell carriers: 2006, use of cytokine induced killer cells to deliver oncolytic vaccinia virus to tumor, resulting in synergistic antitumor activity, (3) Shielding: 2008, Polymer coating and retargeting of oncolytic adenovirus for ovarian cancer to enhance viral pharmacokinetics, (4) Infectious Nucleic Acid: 2011, delivery of oncolytic picornarvirus using infectious nucleic acid (RNA) to successfully achieve sustained viremia and tumor regression. CLINICAL TRIALS: (1) Activity: 2009, Phase II trial with intralesional injection of oncolytic HSV, OncoVEX (talimogene laherparepvec ), in melanoma patients. 26% complete response (8 out of 50), with durability in both injected and uninjected lesions including visceral sites. Undergoing Phase III evaluation. (2) Viremic Threshold: 2011, Intravenous delivery of JX-594, oncolytic vaccinia virus, in patients with metastatic tumor, demonstrating the need for a viremic threshold to be reached for efficient virus delivery to tumors.