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Oncolytic Virotherapy - Sharpening the Sword for Improved Cancer Treatment Strategies


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Oncolytic Virotherapy - Sharpening the Sword for Improved Cancer Treatment Strategies

Oncolytic viruses (OVs) are therapeutically useful viruses which selectively infect and damage cancerous tissues without causing harm to normal tissues. Every virus has a specific cellular tropism that determines which tissues are preferentially infected, and what disease is caused. For instance, rabies virus damages neurons, HIV damages helper T lymphocytes, hepatitis B virus damages hepatocytes, and influenza virus damages airway epithelium. A number of naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. This probably has more to do with tumor biology than with virus biology as most tumors have evolved not only to avoid immune detection and destruction but also to resist apoptosis and translational suppression, which are the crucial responses used by normal cells to limit a virus infection. OVs can kill infected cancer cells in a number of different ways, ranging from direct virus-mediated cytotoxicity through various cytotoxic immune effector mechanisms.

Cell-death mechanisms: immunogenic cell death is important for cancer therapy

OV-mediated cell death does not fit exactly into one of the three classical categories of cell death (apoptosis, autophagy and necrosis), and likewise cell-death pathways induced by chemotherapy can vary from agent to agent. Apoptosis is important for development and the maintenance of tissue homeostasis, and is usually considered to be a nonimmunogenic form of cell death, while necrosis, which is less coordinated and results in the release of proinflammatory cytokines, has been regarded as immunogenic. Nevertheless, it is now clear that the boundaries between each classical cell-death pathway are not defined and there is often overlap. This has been demonstrated through the discovery of “immunogenic” apoptosis in tumor cells, which can be induced by specific chemotherapies, such as the anthracyclines and oxaliplatin (Figure 1).

Likewise, OV-mediated cell death does not fit into either necrosis or apoptosis, but displays features of both, with variations between oncolytic viral types. Generally, the immunogenic death of cancer cells involves a multistep process, beginning with the recognition of pathogen-associated molecular components, such as viral components, which cause such molecules as nucleotides, fractalkine, and ATP to be released, which in turn attract phagocytes or dendritic cells (DCs), and the expression of such signals as phosphatidylserine and calreticulin which aid recognition by phagocytes or DCs. Eventually, danger-associated molecular patterns (DAMPs), such as HMGB1, are expressed. This enables dying tumor cells to lose the ability to induce tolerance and stimulate powerful anticancer immune responses (Figure 1).

A summary of immunogenic cell death (ICD) caused by oncolytic virus and/or chemotherapy.

Figure 1. A summary of immunogenic cell death (ICD) caused by oncolytic virus and/or chemotherapy.

Clinical development

The idea of using viruses to treat cancer first began to take hold in the 1950s, when tissue culture systems and rodent cancer models were originally developed. Hundreds of cancer patients were treated with impure oncolytic virus preparations administered by almost every imaginable route. The viruses were usually arrested by the immune system and did not affect tumor growth, but sometimes infection took hold and tumors regressed, especially in immunosuppressed patients, although they frequently became sick or died when the infection spread to normal tissues. The modern era of oncolytic virotherapy, in which virus genomes are engineered to enhance their antitumor specificity, began with a 1991 publication in which a thymidine kinase–­negative HSV with attenuated neurovirulence was shown to be active in a murine glioblastoma model. Since that first application of virus engineering to an oncolytic HSV, the pace of clinical activities has accelerated considerably, with a number of ongoing or completed trials using OVs belonging to at least ten different virus families and a steady stream of new OVs entering the clinical arena.

Delivering OVs to the tumor

Although several ongoing trials are emphasizing intratumoral delivery, systemic delivery will be required for treatment of metastatic cancer. The goal of systemic therapy is to exceed the ‘viremic threshold’ above which the virus nucleates a critical number of intratumoral infectious centers whose expansion and coalescence lead to tumor destruction. Therefore, current research is focused on minimizing oncolytic virus sequestration in the spleen and liver, evading neutralization by serum factors, targeting viruses to the vascular endothelial cells lining tumor blood vessels and selectively enhancing vessel permeability (Figure. 2).

Barriers to efficient oncolytic virus delivery via the bloodstream and solutions to circumvent them.

Figure 2. Barriers to efficient oncolytic virus delivery via the bloodstream and solutions to circumvent them.

Enhancing intratumoral spread of OVs

Mammalian cells have evolved to resist virus infections (Figure 3). A typical infection involves attacks on cellular defenses by viral gene products (virulence proteins), defensive parries by the host cell through the elaboration of antiviral proteins and further counterattacks by the virus. Viral virulence genes encode proteins which suppress host defense systems, facilitate virus spread between cells and usurp cell metabolic processes. OVs are selected or engineered to be attenuated in normal tissues, often by mutation or deletion of virus virulence genes.

Factors constraining intratumoral virus spread and solutions to circumvent them.

Figure 3. Factors constraining intratumoral virus spread and solutions to circumvent them.

Therefore, an oncolytic virus entering a normal cell triggers the cellular antiviral response but cannot counterattack, so the infection is quickly eliminated. The antiviral response involves production of proteins that counteract the virus through acting directly against the virus, communicating with adjacent cells or jump-starting apoptotic programs. Type I interferons and their receptors are crucial players in this antiviral response, reprogramming the physiological properties of infected and surrounding cells, providing antiangiogenic signals, inducing cell cycle arrest, promoting apoptosis, inhibiting protein synthesis and activating the immune system. There are several approaches to enhancing intratumoral spread of OVs, including:

  • Promoting viral growth by genetic arming and chemical sensitizers;
  • Improving virus spread in tumors;
  • Engineering tumor selectivity into oncolytic virus backbones;
  • Controlling adaptive immunity and clearance of OVs;
  • Enhancing antitumor immunity.

OVs are structurally and biologically diverse, spreading through tumors and killing tumor cells by a series of mechanisms and with different kinetics. Due to their large size and immunogenicity, they are constrained by physical barriers and by host immunity, but they can also cross-prime and amplify antitumor immunity, serving as a cancer immunotherapy. Looking beyond the expected clinical approval of OVs as single agents, there is enormous scope for the development of more complex protocols to achieve superior treatment outcomes. Preclinical studies provide a strong basis for this assertion, demonstrating many synergistic interactions which can overcome the various barriers constraining OVs, such as the use of cell carriers to optimize virus delivery or of immunosuppressive drugs to enhance their intratumoral spread. In recent years, elucidation of the intracellular signaling pathways of innate immunity has been progressing rapidly, so the stage is set for this important area of drug discovery.

References:

  1. Sobol P T, et al. Adaptive Antiviral Immunity Is a Determinant of the Therapeutic Success of Oncolytic Virotherapy. Molecular Therapy, 2011, 19(2):335-344.
  2. Simpson G R, et al. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances. Oncolytic Virotherapy, 2016, 5(Issue 1):1-13.
  3. Zamarin D, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Science Translational Medicine, 2014, 6(226):226ra32.
  4. Russell S J, et al. Oncolytic virotherapy. Nature Biotechnology, 2012, 30:658-670.
  5. Workenhe S T, Mossman K L. Oncolytic Virotherapy and Immunogenic Cancer Cell Death: Sharpening the Sword for Improved Cancer Treatment Strategies. Molecular Therapy, 2014, 22(2):251-256.
  6. Ribas A, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell, 2017, 170(6):1109-1119.

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