Reolysin

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Reolysin® (pelareorep; Wild-Type Reovirus; Serotype 3 Dearing; Oncolytics Biotech), is a proprietary formulation of the human reovirus (reovirus) being developed for the treatment of various cancers and cell proliferative disorders.[1] Reolysin is classified as an oncolytic virus, a virus that preferentially lyses cancer cells. Clinical trials have demonstrated that Reolysin may have activity across a variety of cancer types when administered alone and in combination with other cancer therapies.[2][3][4][5][6][7][8]

In April 2015, the US FDA granted Orphan Drug Designation to Reolysin for malignant glioma.[9]

Clinical trials[edit]

Completed trials[edit]

Reolysin has been evaluated in phase II clinical trials in head & neck, melanoma, pancreatic, lung, ovarian, and colorectal cancers. The trial drug has successfully completed a number of phase I and II clinical trials across a variety of cancer types.[10][11]

Phase II[edit]

Reolysin was tested in combination with docetaxel for metastatic prostate cancer in a phase II trial. The study was completed in early 2016, but results have yet to be presented.[12] Another phase II trial was completed in early 2016 combining reolysin with docetaxel or pemetrexed in patients with NSCLC. Results are still pending.[13]

For treatment of metastatic melanoma, Reolysin was combined with paclitaxel and carboplatin in a phase II trial.[14]

Phase III[edit]

A phase III trial of Reolysin in combination with paclitaxel and carboplatin for treatment of squamous cell carcinoma of the head and neck was completed in May 2014.[15]

Ongoing trials[edit]

A number of clinical phase II and phase III trials are underway in a range of indications including squamous cell carcinoma of the lung, non-small cell lung cancer, pancreatic cancer, and ovarian cancer. The Company is also conducting a phase I trial in colorectal cancer.[16]

A phase II trial of reolysin and paclitaxel combination therapy for metastatic breast cancer is taking place in Canada and expected to be completed in December 2016.[17]

The Gynecologic Oncology Group (GOG), a US-based national non-profit organization, is conducting a phase II trial of paclitaxel with Reolysin in patients with persistent or recurrent, ovarian, fallopian tube or primary peritoneal cancer (GOG186H).[18] This study has been approved and will be sponsored by the Cancer Therapy Evaluation Program,[19] Division of Cancer Treatment and Diagnosis, U.S. National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH), under its Clinical Trials Agreement with Oncolytics.[when?]

Reolysin in combination with FOLFOX6 and bevacizumab is being evaluated in metastatic colorectal cancer (ClinicalTrials.gov Identifier: NCT01622543[20]). The study started in August 2012 and enrolled 109 patients. As of January 2016 it is estimated to completed by March 2017 (with an estimated Primary Completion date in Sept 2016).

For patients with KRAS-mutant metastatic colorectal cancer, Oncyolytics is recruiting patients for phase I trial combining Reolysin with Irinotecan/Fluorouracil/Leucovorin (FOLFIRI).[21]

Mechanism of action[edit]

Reovirus, an acronym for Respiratory Enteric Orphan virus, generally infects mammalian respiratory and bowel systems.[22] Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms.[23]

Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it reproduces well in certain cancer cell lines.[24][25][26] It has since been shown to replicate specifically in cells that have an activated Ras (a cellular signaling pathway that is involved in cell growth and differentiation) with very little effect in cells that do not have active Ras pathways.[27] Reovirus replicates in and eventually kills Ras-activated tumour cells, and as cell death occurs, progeny virus particles are then free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed.[28] Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two thirds of all human cancers,including most metastatic disease, which suggests that Reolysin may be an effective therapeutic for many Ras-activated tumor types and potentially for some cell proliferative disorders.[29][30][31]

See also[edit]

References[edit]

  1. ^ Lal, R; Harris, D; Postel-Vinay, S; De Bono, J (2009). "Reovirus: Rationale and clinical trial update". Current opinion in molecular therapeutics. 11 (5): 532–9. PMID 19806501. 
  2. ^ Sei, S; Mussio, JK; Yang, QE; Nagashima, K; Parchment, RE; Coffey, MC; Shoemaker, RH; Tomaszewski, JE (2009). "Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells". Molecular cancer. 8: 47. doi:10.1186/1476-4598-8-47. PMC 2723073Freely accessible. PMID 19594950. 
  3. ^ Twigger, K; Vidal, L; White, CL; De Bono, JS; Bhide, S; Coffey, M; Thompson, B; Vile, RG; et al. (2008). "Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy". Clinical Cancer Research. 14 (3): 912–23. doi:10.1158/1078-0432.CCR-07-1400. PMID 18245555. 
  4. ^ Pandha, HS; Heinemann, L; Simpson, GR; Melcher, A; Prestwich, R; Errington, F; Coffey, M; Harrington, KJ; Morgan, R (2009). "Synergistic effects of oncolytic reovirus and cisplatin chemotherapy in murine malignant melanoma". Clinical Cancer Research. 15 (19): 6158–66. doi:10.1158/1078-0432.CCR-09-0796. PMID 19773377. 
  5. ^ Harrington, KJ; Karapanagiotou, EM; Roulstone, V; Twigger, KR; White, CL; Vidal, L; Beirne, D; Prestwich, R; et al. (2010). "Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers". Clinical Cancer Research. 16 (11): 3067–77. doi:10.1158/1078-0432.CCR-10-0054. PMC 3907942Freely accessible. PMID 20484020. 
  6. ^ Smakman, N; Van Der Bilt, JD; Van Den Wollenberg, DJ; Hoeben, RC; Borel Rinkes, IH; Kranenburg, O (2006). "Immunosuppression promotes reovirus therapy of colorectal liver metastases". Cancer gene therapy. 13 (8): 815–8. doi:10.1038/sj.cgt.7700949. PMID 16543920. 
  7. ^ Kottke, T; Thompson, J; Diaz, RM; Pulido, J; Willmon, C; Coffey, M; Selby, P; Melcher, A; et al. (2009). "Improved Systemic Delivery of Oncolytic Reovirus to Established Tumors Using Preconditioning with Cyclophosphamide-Mediated Treg Modulation and Interleukin-2". Clinical Cancer Research. 15 (2): 561–9. doi:10.1158/1078-0432.CCR-08-1688. PMC 3046733Freely accessible. PMID 19147761. 
  8. ^ E Karapanagiotou, H.S Pandha, G Hall, J Chester et al., Phase I/II trial of oncolytic reovirus (REOLYSIN) in combination with carboplatin/paclitaxel in patients with advanced solid cancers with emphasis on squamous cell carcinoma of the head and neck (SCCHN), AACR EORTC Poster (2009) Boston.Poster
  9. ^ Oncolytics Biotech (ONCY) Announces Receipt of FDA Orphan Drug Designation for REOLYSIN. April 2015
  10. ^ REO 017 Meets Primary Endpoint for First Part of U.S. Phase II Pancreatic Cancer Clinical Trial - Onco'Zine - The International Cancer Network [1]
  11. ^ Oncolytics Biotech® Inc. Collaborators to Present Positive Phase 2 REOLYSIN Clinical Data in Pancreatic Cancer at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference [2]
  12. ^ https://clinicaltrials.gov/ct2/show/NCT01619813
  13. ^ https://clinicaltrials.gov/ct2/show/NCT01708993
  14. ^ https://clinicaltrials.gov/ct2/show/NCT00984464
  15. ^ https://clinicaltrials.gov/ct2/show/results/NCT01166542
  16. ^ Clinical Trials Overview
  17. ^ https://clinicaltrials.gov/ct2/show/NCT01656538?
  18. ^ Randomized Phase II Ovarian Cancer Study With Reolysin® To Be Conducted By The Gynecologic Oncology Group (GOG)[3]
  19. ^ Cancer Therapy Evaluation Program
  20. ^ Reolysin in Combination With FOLFOX6 and Bevacizumab or FOLFOX6 and Bevacizumab Alone in Metastatic Colorectal Cancer ClinicalTrials.gov Id: NCT01622543
  21. ^ https://clinicaltrials.gov/ct2/show/NCT01274624
  22. ^ M.L Nirbert, L.A Schiff, B.N Fields, Reoviruses and their Replication, in: Fields B.N, Knipe D.M, Howley P.M (Eds.), Fundamental Virology, third ed., Lippincott-Raven Publishers, Philadelphia 1996. Page=691-730
  23. ^ White, CL; Twigger, KR; Vidal, L; De Bono, JS; Coffey, M; Heinemann, L; Morgan, R; Merrick, A; et al. (2008). "Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial". Gene therapy. 15 (12): 911–20. doi:10.1038/gt.2008.21. PMID 18323793. 
  24. ^ Thirukkumaran, C; Morris, DG (2009). "Oncolytic viral therapy using reovirus". Methods in molecular biology (Clifton, N.J.). Methods in Molecular Biology. 542: 607–34. doi:10.1007/978-1-59745-561-9_31. ISBN 978-1-934115-85-5. PMID 19565924. 
  25. ^ Duncan, MR; Stanish, SM; Cox, DC (1978). "Differential sensitivity of normal and transformed human cells to reovirus infection". Journal of Virology. 28 (2): 444–9. PMC 354293Freely accessible. PMID 214572. 
  26. ^ Hashiro, G; Loh, PC; Yau, JT (1977). "The preferential cytotoxicity of reovirus for certain transformed cell lines". Archives of Virology. 54 (4): 307–15. doi:10.1007/BF01314776. PMID 562142. 
  27. ^ Strong, JE; Coffey, MC; Tang, D; Sabinin, P; Lee, PW (1998). "The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus". The EMBO Journal. 17 (12): 3351–62. doi:10.1093/emboj/17.12.3351. PMC 1170673Freely accessible. PMID 9628872. 
  28. ^ Nagano, S; Perentes, JY; Jain, RK; Boucher, Y (2008). "Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors". Cancer Research. 68 (10): 3795–802. doi:10.1158/0008-5472.CAN-07-6193. PMC 2871708Freely accessible. PMID 18483263. 
  29. ^ Bos, JL (1989). "Ras oncogenes in human cancer: a review". Cancer Research. 49 (17): 4682–9. PMID 2547513. 
  30. ^ Duursma, AM; Agami, R (2003). "Ras interference as cancer therapy". Seminars in cancer biology. 13 (4): 267–73. doi:10.1016/S1044-579X(03)00040-3. PMID 14563121. 
  31. ^ Norman, KL; Lee, PW (2005). "Not all viruses are bad guys: the case for reovirus in cancer therapy". Drug Discovery Today. 10 (12): 847–55. doi:10.1016/S1359-6446(05)03483-5. PMID 15970267. 

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