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Oncolytic Virotherapy

Oncolytic Virotherapy. Reovirus : A Prototypical Wild-type Oncolytic Virus. By: Stephen Mayper. Cancer. Abnormal cell growth Accumulated genetic & epigenetic alterations Healthy cells gone “haywire” Numerous means of immune response evasion. Conventional Treatments. Surgery.

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Oncolytic Virotherapy

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  1. Oncolytic Virotherapy Reovirus: A Prototypical Wild-type Oncolytic Virus By: Stephen Mayper

  2. Cancer Abnormal cell growth Accumulated genetic & epigenetic alterations Healthy cells gone “haywire” Numerous means of immune response evasion

  3. Conventional Treatments Surgery • Tumor removal • Is ineffective against and can induce metastasis • Inherent risk!

  4. Conventional Treatments Radiotherapy (Creative representation if innocent bystander cell death…) • Uses radiation to kill tumor cells • Effective at reducing… • …Tumors! • …Aaaaand healthy cells • Can carry severe side effects

  5. Conventional Treatments Chemotherapy • Use of pharmaceuticals to kill tumor cells • It works! • …But it kills lots of other cells indiscriminately

  6. Emerging Treatment: Virotherapy • Uses an oncolyticvirus (OV) to lyse cancer cells • Advantages: • High specificity means fewer side effects • Self-regulating dosage • Lack of contraindications

  7. Viruses currently being explored Seneca Valley virus SV40 virus Adenovirus Parvo virus Myxoma virus Mumps virus Influenza virus Human Herpes virus Pseudorabies virus Vaccinia virus Coxsackie A virus

  8. How does it work? …Get it? (It’s a virus in “nature!”) • Virus can be… • Naturally occurring • Genetically engineered • Transcription targeting • Attenuation • Specificity generally determined by antiviral pathway deregulation

  9. Example: Adenovirus Therapy Targeting Gliomas Source: Maruniak, Jim. "Adenovirus." MCB 5505, Honors Virology. University of Florida, Gainesville, FL. 19 Feb. 2011. Lecture.

  10. Another Mechanism of Tumor Cell OV Susceptibility Source: Chiocca EA. Oncolytic viruses. Nat Rev Cancer. 2002 Dec;2(12):938-50.

  11. Reovirus

  12. Reovirus Background • REOvirus = “Respiratory Enteric Orphan Virus” • Infect human respiratory & gastrointestinal tracts • “Orphaned” because originally not thought to be associated with any disease • Several disease associations discovered since • Reoviruses are pervasive

  13. Reovirus Taxonomy • African Horse Sickness • Colorado Tick Fever • Blue Tongue Disease Mostly Asymptomatic (Percentage of gastroenteritis deaths) • Family: Reoviridae • Genera Infecting Vertebrates (6) • Orthoreovirus • Orbivirus • Coltivirus • Rotavirus • Aquareovirus • Seadornavirus Source: Cann, Alan. "Reoviruses." MicrobiologyBytes. 11 Sept. 2007. Web. <http://www.microbiologybytes.com/virology/Reoviruses.html>.

  14. Reovirus Structure • Spherical, 80 nm diameter • Non-enveloped • Isometric capsid • Concentric inner and outer capsids • Sometimes middle capsid • (Inner capsid = “core”) • 4 core proteins • λ-1, λ-3, μ-2, σ-2 • Heat-stable • Stable @ pH= 3 – 9 • Denatured by ethanol

  15. Reovirus Genome RNA Double-Stranded Linear 10-12 segments (species-dependent) Reassortment common in vitro Encodes viral replication machinery Source: http://education.expasy.org/images/Orthoreovirus_genome.jpg

  16. Reovirus Reproduction • Replicates in the cytoplasm • Encodes its own replication machinery • Antiviral susceptibility • Does NOT fully uncoat • Core is resistant to protease digestion • No uncoating • No destruction by host cell • Genomic RNA stays in the core • Assembled virions form cytoplasmic inclusion bodies • Released via cell lysis • 6 – 7 hour replication time

  17. Reovirus Replication Illustrated

  18. Questions?Comments?

  19. Sources • Cann, Alan. "Reoviruses." MicrobiologyBytes. 11 Sept. 2007. Web. <http://www.microbiologybytes.com/virology/Reoviruses.html>. • Chiocca EA. Oncolytic viruses. Nat Rev Cancer. 2002 Dec;2(12):938-50. • Hammill AM, Conner J, Cripe TP. Oncolyticvirotherapy reaches adolescence. Pediatr Blood Cancer. 2010 Dec 15;55(7):1253-63. doi: 10.1002/pbc.22724. Epub 2010 Aug 23. • Maruniak, Jim. "Adenovirus." MCB 5505, Honors Virology. University of Florida, Gainesville, FL. 19 Feb. 2011. Lecture. • Mertens P. The dsRNA viruses. Virus Res. 2004 Apr;101(1):3-13. • Nettelbeck DM. Cellular genetic tools to control oncolytic adenoviruses for virotherapy of cancer. J Mol Med. 2008 Apr;86(4):363-77. Epub 2007 Dec 19. • Siegel, Robert. "Reoviruses." Stanford University. 1 Feb. 1999. Web. 20 Apr. 2011. <http://www.stanford.edu/group/virus/1999/caryn/reovirus.html>. • Vähä-Koskela MJ, Heikkilä JE, Hinkkanen AE. Oncolytic viruses in cancer therapy. Cancer Lett. 2007 Sep 8;254(2):178-216. Epub 2007 Mar 23.

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