Article series: Cancer immunotherapy

Oncolytic viruses: a new class of immunotherapy drugs

Journal name:
Nature Reviews Drug Discovery
Year published:
Published online
Corrected online


Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.

At a glance


  1. Oncolytic viruses can exploit cancer immune evasion pathways.
    Figure 1: Oncolytic viruses can exploit cancer immune evasion pathways.

    a | Following viral infection, most normal cells activate an antiviral pathway that allows to contain viral infections. The antiviral machinery can be triggered by viral pathogen-associated molecular patterns (PAMPs) that activate Toll-like receptors (TLRs) or through the detection of viral nucleic acids by retinoic acid-inducible gene 1 (RIG-1). Once a virus is detected, a signalling cascade through several type I interferon (IFN) elements (Janus kinase (JAK), signal transducer and activator of transcription (STAT), and interferon regulatory factor 9 (IRF9)) results in a programmed transcriptional pathway that limits viral spread and can target infected cells for apoptosis or necrosis. Local IFN production induced by the innate immune response to viral infections may also promote antiviral activity through the IFN receptor (IFNR). TLRs signal via the myeloid differentiation primary response protein MYD88, TIR-domain-containing adapter-inducing IFNβ (TRIF), IRF7, IRF3 and nuclear factor-κB (NF-κB), inducing the production of pro-inflammatory cytokines and type I IFNs. The type I IFNs signal through the JAK–STAT signalling pathway, resulting in the upregulation of cell cycle regulators, such as protein kinase R (PKR) and IRF7, which limit viral spread by binding to viral particles and triggering type I IFN transcriptional pathways, promoting abortive apoptosis of infected cells and the production of cytokines that alert the immune system to the presence of a viral infection. b | In cancer cells, however, this process is disrupted. Cancer cells may downregulate key signalling components within the innate signalling pathway, including RIG-1, IRF7, and IRF3 (Ref. 1). This limits detection of viral particles by TLR and RIG-1, making cancer cells more susceptible to viral replication. Furthermore, cancer cells may downregulate key components of the type I IFN signalling pathway2, 3, 4, 5, 6, 7, thereby limiting the pro-apoptotic and cell cycle regulatory effects of type I IFNs. Although data are limited, the figure depicts individual viruses near the factors and/or pathways that are known to promote viral elimination in normal cells (part a) or that support viral replication owing to factor deficiency in cancer cells (part b). dsRNA, double-stranded RNA; NDV, Newcastle disease virus; TRAF, TNF-associated factor; VSV, vesicular stomatitis virus.

  2. The induction of local and systemic anti-tumour immunity by oncolytic viruses.
    Figure 2: The induction of local and systemic anti-tumour immunity by oncolytic viruses.

    The therapeutic efficacy of oncolytic viruses is determined by a combination of direct cancer cell lysis and indirect activation of anti-tumour immune responses. Upon infection with an oncolytic virus, cancer cells initiate an antiviral response that consists of endoplasmic reticulum (ER) and genotoxic stress. This response leads to the upregulation of reactive oxygen species (ROS) and the initiation of antiviral cytokine production. ROS and cytokines, specifically type I interferons (IFNs), are released from the infected cancer cell and stimulate immune cells (antigen presenting cells, CD8+ T cells, and natural killer (NK) cells). Subsequently, the oncolytic virus causes oncolysis, which releases viral progeny, pathogen-associated molecular patterns (PAMPs), danger-associated molecular pattern signals (DAMPs), and tumour associated antigens (TAAs) including neo-antigens. The release of viral progeny propagates the infection with the oncolytic virus. The PAMPs (consisting of viral particles) and DAMPs (comprising host cell proteins) stimulate the immune system by triggering activating receptors such as Toll-like receptors (TLRs). In the context of the resulting immune-stimulatory environment, TAAs and neo-antigens are released and taken up by antigen presenting cells. Collectively, these events result in the generation of immune responses against virally infected cancer cells, as well as de novo immune responses against TAAs/neo-antigens displayed on un-infected cancer cells. CD40L, CD40 ligand; dsRNA, double-stranded RNA; HMGB1, high mobility group box 1; HSP, heat shock protein; IL-2, interleukin-2; IL-2R, IL-2 receptor; MHC, major histocompatibility complex; ssRNA, single-stranded RNA; TCR, T cell receptor; TNFα, tumour necrosis factor-α.

  3. Mechanisms of viral entry into cancer cells.
    Figure 3: Mechanisms of viral entry into cancer cells.

    Oncolytic viruses utilize several mechanisms to enter host cells, including cell surface receptors that are frequently overexpressed on cancer cells. Some viruses are able to via more than one receptor and some receptors can promote the entry of more than one type of virus. Some viruses use endocytosis through membrane fusion and syncytia formation to enter cells. Certain oncolytic viruses are known to preferentially target cancer cells but the cell surface receptor for entry has not been identified. CAR, coxsackievirus-adenovirus receptor; DAF, decay accelerating factor; HVEM1, herpesvirus entry mediator 1; ICAM-1, intercellular adhesion molecule 1; LDLR, low-density lipoprotein receptor; NDV, Newcastle disease virus; SARs, sialic acid receptors; SLAM, signalling lymphocytic activation molecule; VSV, vesicular stomatitis virus (VSV).

  4. Oncolytic viruses can target oncogenic pathways.
    Figure 4: Oncolytic viruses can target oncogenic pathways.

    The expression of oncogenes and other aberrant host cell proteins in cancer cells can promote viral replication and oncolytic activity. a | In healthy cells, regulation of cell cycle entry and proliferation is provided by key factors, such as protein kinase R (PKR), p16, retinoblastoma (Rb), and the tumour suppressor p53. These elements promote abortive apoptosis when the cell cycle is dysregulated. PKR may also help to regulate transcription and induce abortive apoptosis when cells are infected with a virus. b | In cancer cells, cell cycle regulation and cellular proliferation are typically disrupted due to the activity of oncogenes and the loss of tumour suppressor genes. These changes can support viral replication and promote oncolytic virus-induced cell death. For example, activating mutations in the small GTPase RAS increase cell proliferation, which is accompanied by increased protein production. This process can be usurped by oncolytic viruses to replicate more efficiently, as reported for Newcastle disease virus (NDV) and vesicular stomatitis virus (VSV). Furthermore, hyperactive RAS blocks PKR, a process that can facilitate the selective replication of oncolytic viruses (such as reovirus, herpes simplex virus type 1 (HSV-1), adenovirus, vaccinia virus and influenza virus), in RAS-mutant cancer cells. Some viruses, such as adenovirus, reovirus and parvovirus, preferentially target p53-mutant or p53-null cancer cells because healthy cells with intact p53 undergo abortive apoptosis upon infection. Likewise, aberrant expression of Rb and p16, which regulate cell cycle entry, can render cancer cells susceptible to oncolytic viruses such as adenovirus, HSV-1, vaccinia virus and reovirus. Cancer cells also frequently upregulate the anti-apoptotic protein B cell lymphoma-XL (BCL-XL). This process confers a selective advantage for oncolytic viruses such as NDV, as it allows more time for viral replication. CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; PDGFR, platelet-derived growth factor receptor.

Change history

Corrected online 18 January 2016
In the original article, some descriptions of the properties of viruses in Tables 1 and 2 were inaccurate; the tables have been updated to reflect this. Also, on page 656, Newcastle Disease Virus (NDV) was accidentally described as a double-stranded RNA virus. NDV is a single-stranded RNA virus.
The authors would like to acknowledge R. C. Hoeben and B. G. van den Hoogen for alerting them to these errors.


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  1. Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, New Jersey 08901, USA.

    • Howard L. Kaufman,
    • Frederick J. Kohlhapp &
    • Andrew Zloza

Competing interests statement

H.L.K. serves as a consultant for Amgen and has received honoraria. The other authors have no competing interests to disclose.

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  • Howard L. Kaufman

    Howard L. Kaufman received his M.D. from Loyola University, Chicago, Illinois, USA, in 1986 and completed his residency training in general surgery at Boston University, USA, in 1995. He completed fellowships in tumour immunology and surgical oncology at the US National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. He began his career as an Assistant Professor at the Albert Einstein College of Medicine, Yeshiva University, New York, USA, in 1997 and became an Associate Professor and Chief, Division of Surgical Oncology at Columbia University, New York, USA, in 2001. He became a tenured full professor at Rutgers University, New Brunswick, New Jersey, USA, in 2014. He is currently the Associate Director for Clinical Science at the Rutgers Cancer Institute of New Jersey and Chief of the Division of Surgical Oncology at the Rutgers Robert Wood Johnson Medical School. He runs an active translational research programme focused on the development of oncolytic viruses for the treatment of melanoma, serving as the principal investigator or responsible investigator for over 15 active local and national clinical protocols. He has published more than 30 textbook chapters and 150 original research papers. He was elected President of the Society for Immunotherapy of Cancer and serves on the executive committee for the Commission on Cancer.

  • Frederick J. Kohlhapp

    Frederick J. Kohlhapp received his Ph.D. in Immunology from the University of Chicago, Chicago, Illinois, USA, in 2012. He completed an F32-funded Postdoctoral Fellowship at Northwestern University, Chicago, Illinois, USA, in 2014, and is currently a Kirby Foundation Postdoctoral Fellow at the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. His research focuses on the tumour microenvironment, specifically on the effects of immunotherapy and oncolytic viruses on altering anti-tumour immune responses and antigen presentation.

  • Andrew Zloza

    Andrew Zloza obtained his Ph.D. in Immunology/Microbiology in 2006 and his M.D. in 2009 through the Rush Physician Scientist MD PhD Program at Rush University Medical Center, Chicago, Illinois, USA. He completed a T32-funded postdoctoral fellowship in tumour immunology and cancer vaccine design at the University of Chicago, Chicago, Illinois, USA, in 2011. In 2012, he joined the faculty of the Department of Immunology and Department of Internal Medicine at Rush University Medical Center, Chicago, Illinois, USA. He is currently the Section Chief of Surgical Oncology Research at the Rutgers Cancer Institute of New Jersey and Assistant Professor in the Department of Surgery at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. He leads an active basic science and translational research programme focusing on the natural role of infections in modifying anti-tumour immune responses and on the development of humanized mouse models.

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