Reolysin

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

Completed trials

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]

Ongoing trials

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.[12]

Gynecologic malignancies

The Gynecologic Oncology Group (GOG), a US-based national non-profit organization, is conducting a randomized Phase II trial of weekly paclitaxel versus weekly paclitaxel with Reolysin in patients with persistent or recurrent, ovarian, fallopian tube or primary peritoneal cancer (GOG186H).[13] This study has been approved and will be sponsored by the Cancer Therapy Evaluation Program,[14] 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.

Squamous Cell Carcinoma of the Head and Neck

Initial top line data from the first endpoint in a clinical study examining Reolysin, in combination with carboplatin and paclitaxel in second-line patients with platinum-refractory, taxane-naïve head and neck cancers (an amended version of a previously double-blinded randomized Phase III trial; NCT01166542[15]) were presented in December 2012 showing that patients with metastatic only disease appeared to have a better response to Reolysin than chemotherapy alone in the sub-set of patients evaluated, although many patients were excluded from the analysis due to leaving the study before the first required assessment scan (more patients in the Reolysin arm than in the chemotherapy only arm were excluded for this reason).[16]

The purpose of this trial is to evaluate overall survival and progression free survival following intravenous administration of Reolysin in combination with paclitaxel and carboplatin versus chemotherapy treatment alone, in patients with metastatic or recurrent Squamous Cell Carcinoma of the Head and Neck.

Metastatic Colorectal Cancer

Reolysin in combination with FOLFOX6 and Bevacizumab or FOLFOX6 and Bevacizumab alone is also evaluated in metastatic colorectal cancer (ClinicalTrials.gov Identifier: NCT01622543[17]). The purpose of this trial is to find out if reolysin in combination with FOLFOX6/ bevacizumab offers better results than standard therapy with FOLFOX6/ bevacizumab. 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).

Mechanism of action

Reovirus, an acronym for Respiratory Enteric Orphan virus, generally infects mammalian respiratory and bowel systems.[18] Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms.[19]

Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it reproduces well in certain cancer cell lines.[20][21][22] 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.[23] 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.[24] 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.[25][26][27]

See also

References

  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 2723073. 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 : an official journal of the American Association for 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 : an official journal of the American Association for 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 : an official journal of the American Association for Cancer Research 16 (11): 3067–77. doi:10.1158/1078-0432.CCR-10-0054. PMC 3907942. 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 : an official journal of the American Association for Cancer Research 15 (2): 561–9. doi:10.1158/1078-0432.CCR-08-1688. PMC 3046733. 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
  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
  12. ↑ Clinical Trials Overview
  13. ↑ Randomized Phase II Ovarian Cancer Study With Reolysin® To Be Conducted By The Gynecologic Oncology Group (GOG)
  14. ↑ Cancer Therapy Evaluation Program
  15. ↑ Efficacy Study of REOLYSIN® in Combination With Paclitaxel and Carboplatin in Platinum-Refractory Head and Neck Cancers
  16. ↑ Positive Top Line Data Presented for Reolysin® in Randomized Phase III Study in Head and Neck Cancers
  17. ↑ Reolysin in Combination With FOLFOX6 and Bevacizumab or FOLFOX6 and Bevacizumab Alone in Metastatic Colorectal Cancer ClinicalTrials.gov Id: NCT01622543
  18. ↑ 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
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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 354293. PMID 214572.
  22. ↑ 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.
  23. ↑ 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 1170673. PMID 9628872.
  24. ↑ 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 2871708. PMID 18483263.
  25. ↑ Bos, JL (1989). "Ras oncogenes in human cancer: a review". Cancer Research 49 (17): 4682–9. PMID 2547513.
  26. ↑ 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.
  27. ↑ 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.

External links

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