Oncolytic Viruses

4 Key excerpts on "Oncolytic Viruses"

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  eBook - ePub

  Principles of Virology, Volume 2

  Pathogenesis and Control

  • S. Jane Flint, Vincent R. Racaniello, Glenn F. Rall, Theodora Hatziioannou, Anna Marie Skalka(Authors)
  • 2020(Publication Date)
  • ASM Press

    (Publisher)

  9.4. Oncolytic Viruses are typically human viruses engineered to take advantage of the alterations in production or function of gene products and pathways that lead to the appearance of these hallmarks. However, some viruses that do not normally infect humans, which therefore do not possess preexisting antibodies against them, can nevertheless reproduce well in cancer cells. This property is exemplified by vesicular stomatitis virus (a rhabdovirus that infects domestic animals, such as horses and cattle) and Newcastle disease virus (a paramyxovirus that infects birds, including chickens). For example, wild-type vesicular stomatitis virus is quite sensitive to type I interferon, but this innate antiviral defense is impaired in many types of tumor cells. Furthermore, tumor cell selectivity can be increased by mutations that prevent synthesis of the viral M protein, which blocks expression of interferon-stimulated genes in infected cells (Chapter 3). Increased production of cell surface proteins associated with tumor cell tissue invasion and metastasis can enhance sensitivity to infection by some human viruses. For example, many tumor cells display on their surfaces increased quantities of CD46, one of several receptors for measles virus and the receptor that is most effectively recognized by the measles virus vaccine strain. Similarly, increased production of DAF (decay accelerating factor), which with ICAM-1 (intercellular adhesion molecule 1) forms the receptor for the picornavirus Coxsackievirus A21, is characteristic of some tumor cells, including melanoma cells. Consequently, these viruses enter tumor cells more efficiently than they do normal human cells. Figure 9.4 Properties of cancer cells that can facilitate reproduction of Oncolytic Viruses. Common properties of cancer cells, often called cancer hallmarks, are listed at the left. Examples of Oncolytic Viruses are indicated at the right with their icons

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  eBook - ePub

  Virus Bioinformatics

  • Dmitrij Frishman, Manja Marz(Authors)
  • 2021(Publication Date)
  • Chapman and Hall/CRC

    (Publisher)

  12

  The Potential of Computational Genomics in the Design of Oncolytic Viruses

  Henni Zommer and Tamir Tuller Tel-Aviv University

  Contents

  12.1   Introduction 12.2   Mathematical Modeling of OV 12.3   Computational Modeling of Heterologous Gene Expression and Live Attenuated Vaccines 12.4   The Potential of Bioinformatics and Genomics in the Development of OV 12.5   Conclusion References

  12.1 Introduction

  In the age-old search for a cancer cure, there has been one player lurking in the dark, that every few years rears its head and rocks the world into a state of urgency, the virus. What if we can harness these microscopic yet greatly significant viruses to combat diseases that we face?

  There is a common hope of finding a cure for cancer when the term cancer in essence is used to describe the common symptoms resulting from different causes [1 ], which can be considered as different diseases. It is just like taking medicine for a headache can help reduce the discomfort, but the cause of the headache can be many different things, thus not addressing the cause can result in the pain “reappearing” once the effect of the medication wears off [2 ]. Currently, systemic treatments are used to fight cancer—chemotherapy, radiation therapy, which essentially destroy everything in a nonspecific manner: the healthy, normal cells and tissues alongside the cancer cells. This deems them effective across different cancers, yet they cause great general harm and work productively in only a subset of patients [3 ]; moreover, recurrent cancer is not uncommon [4 ]. Such a complex and dynamic “disease” requires therapy that is dynamic and versatile as well. The search for something effective and specific against cancer has been underway for decades, and one field that after years of research is today plausibly the most promising one with regard to cancer-therapy is Oncolytic Virus Therapy (OVT) [5 , 6 , 7 and 8

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  eBook - ePub

  Advanced Textbook on Gene Transfer, Gene Therapy and Genetic Pharmacology

  Principles, Delivery and Pharmacological and Biomedical Applications of Nucleotide-Based Therapies

  • Daniel Scherman(Author)
  • 2013(Publication Date)
  • ICP

    (Publisher)

  PART III THERAPEUTIC APPLICATIONS 18 ONCOLYTIC ADENOVIRUSES FOR CANCER GENE THERAPY Gunnel Hallden, Yaohe Wang, Han-Hsi Wong and Nick R. Lemoine a 18.1 Cancer and Oncolytic Adenoviruses Cancer is still a leading cause of death in the Western world despite the many efforts to develop new strategies for better treatments and earlier detection. A major problem in treating cancers is the development of resistance to current standard therapeutics, including cytotoxic drugs and radiation therapy. More efficacious therapies with different mechanisms of action to overcome treatment resistance are therefore urgently needed. A relatively novel and promising therapeutic platform is virotherapy with oncolytic adenoviruses. Over the last two decades several engineered viral mutants have been evaluated in clinical trials targeting various tumor types and were demonstrated to be safe, with some efficacy. Oncolytic mutants were specifically engineered to infect, replicate in and lyse tumor cells, leaving normal tissue relatively unharmed (Fig. 18.1). This approach has been applied to numerous viral species, including adenovirus, measles, herpes and poxviruses, to name a few. However, most of the work has focused on adenoviral vectors, especially serotype 5 (Ad5), because of: the ease of genetically engineering its small, linear and well-characterized 36 kb genome (Fig. 18.2a, b); its natural tropism for epithelial cells and the carcinomas derived from them; the lack of integration into the host cell genome; the clinical safety record with only flu-like side effects; and the ease of production under good manufacturing practice (GMP). In addition, no crossresistance with current standard therapies occurs, and on the contrary, early viral genes appear to enhance the apoptosis-inducing effects of other cytotoxic therapies and to reverse resistance. In combination with standard anticancer therapeutics, synergistic cell killing can often be achieved specifically in cancer cells

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  Cancer Chemotherapy

  Basic Science to the Clinic

  • Gary S. Goldberg, Rachel Airley(Authors)
  • 2020(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  131 I which can be used to enhance chemotherapeutic cytotoxic effects on targeted cancer cells. Oncolytic VSVs are being investigated for several cancers including hepatocarcinoma and glioblastoma.

  Parvoviruses contain linear single‐stranded DNA with an average genome size of 5–6 kb that encodes only two genes (hence the Latin name “parvus” meaning “small”). These viruses rely on host machinery and, therefore, require that host cells enter S phase for their replication. This property intrinsically restricts parvovirus infection to proliferating cells – including cancer cells. Another attribute of these viruses is their ability to pass the blood–brain barrier. The wild‐type H1 rat parvovirus strain (H1PV) is being developed as the oncolytic construct “ParvOryx.” The parvovirus nonstructural protein 1 (NS1) induces host cell cycle arrest, apoptosis, and a tumor‐specific immune response. These effects have been reported for cancer cells including pancreatic, prostate, mammary, and pulmonary carcinoma, glioblastoma, melanoma, and lymphoma. ParvOryx is currently being investigated alone and in combination with other compounds including bevacizumab and immune checkpoint inhibitors for glioblastoma and pancreatic cancer.

  Retroviruses contain single‐stranded sense RNA that is transcribed into DNA by viral reverse transcriptase and inserted into the host genome by retroviral integrase after infection. Oncogenic retroviruses such as the Rous sarcoma virus are described in Chapter 4.1. In contrast to these tumor promoters, different retroviral constructs are being engineered as Oncolytic Viruses to combat cancer. For example, vocimagene amiretrorepvec (Toca 511) is derived from murine leukemia virus with insertion of a gene encoding yeast cytosine deaminase. Toca FC, which contains the prodrug 5‐fluorocytosine, is given in combination with the Toca 511 construct. Toca 511 cytosine deaminase converts the 5‐fluorocytosine into 5FU (5‐fluorouracil), which acts as a chemotherapeutic antimetabolite as described in Chapter 9 (see Figure 9.3). Since 5‐fluorocytosine crosses the blood–brain barrier (even though 5FU does not), this technology is being pursued to treat astrocytoma and glioblastoma. In this approach, Toca 511 is injected into the tissues lining the region where a brain tumor was excised, and 5FU from Toca FC is converted to 5FU by cytosine deaminase expressed by infected cells. In addition to the infected cells, 5FU also transfers to noninfected tumor cells by the “bystander effect” as discussed above in section 17.4 (see Figure 17.5

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