Biology:Reolysin

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REOLYSIN® (pelareorep; Wild-Type Reovirus; Serotype 3 Dearing; Oncolytics Biotech Inc.), is a proprietary isolate of the unmodified human reovirus (reovirus) being developed as a first-in-class systemically administered immuno-oncology viral agent for the treatment of solid tumors and hematological malignancies.[1][2] REOLYSIN is classified as an oncolytic virus, a virus that preferentially lyses cancer cells. Based on both single-arm and randomized phase 2 clinical studies, REOLYSIN also promotes an inflamed tumor phenotype through innate and adaptive immune responses.[1] Clinical trials have demonstrated that REOLYSIN may have activity across a variety of cancer types (including breast, colorectal and pancreatic, as well as multiple myeloma) when administered alone and in combination with other cancer therapies.[3][4][5][6][7][8][9] In April 2015, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to REOLYSIN for malignant glioma.[10] In May 2017, the FDA granted Fast Track Designation for REOLYSIN in metastatic breast cancer.[11]

Oncolytics Biotech Inc. (Oncolytics) has more than 415 patents for REOLYSIN issued globally, including more than 60 in the U.S. and 20 in Canada, as well as numerous patents pending worldwide.[12]

Mechanism of action

Reovirus, an acronym for Respiratory Enteric Orphan virus, generally infects mammalian respiratory and bowel systems.[13] Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms.[14]

Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it reproduces well in certain cancer cell lines.[15][16][17] 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.[18] 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.[19] 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.[20][21][22]

In both single-arm and randomized phase 2 clinical studies, REOLYSIN, in combination with various chemotherapeutic agents, has shown a trend to improve overall survival (OS) in certain indications and patient populations, while having a limited impact on objective response rate (ORR) or progression-free survival (PFS), a therapeutic profile consistent with those observed with approved immunotherapies. Based on these observations, Oncolytics believes REOLYSIN has multiple components to its mechanism of action (MOA):

  • Direct tumor lysis – selective viral replication in permissive cancer cells leading to tumor cell lysis;
  • Innate immune response – viral replication resulting in a cascade of chemokines/cytokines causing natural killer (NK) cells to recognize and attack cancer cells; and
  • Adaptive immune response – antigen presenting cells (APCs) display tumor-associated antigens (TAA) and viral-associated antigens (VAA) to educate T-cells to recognize and destroy cancer cells.

Clinical trials

REOLYSIN has been evaluated in numerous clinical trials in variety of cancers, including pancreatic, breast, head and neck, prostate, lung, colorectal, bladder and ovarian cancers.[23]

REOLYSIN's clinical development plan is based on drug combinations that can potentially boost each response of REOLYSIN's mechanism of action, with three development pathways: 1) chemo combinations (direct cell lysis) 2) immunotherapy combinations (adaptive immune response) and; 3) combination with (immunomodulators) IMiDs / targeted therapy (innate immune response).[24]

As part of REOLYSIN's registration pathway, Oncolytics, in partnership with the Canadian Cancer Trials Group (CCTG) (formerly the National Cancer Institute of Canada Clinical Trials Group), is conducting a phase 2 clinical trial in metastatic breast cancer patients receiving standard weekly paclitaxel therapy. In March 2017, the company announced positive overall survival data from the open-label, randomized study where, in the intention-to-treat patient population, there was a statistically significant improvement in median overall survival from 10.4 months on the control arm to 17.4 months on the test arm. In May 2017, Oncolytics announced that the FDA granted Fast Track designation for REOLYSIN for the treatment of metastatic breast cancer, and in September 2017, the company announced a successful End-of-Phase 2 meeting with the FDA.

Oncolytics is conducting its first study of REOLYSIN in combination with a checkpoint inhibitors in an open-label phase 1b trial. The trial will assess the safety and dose-limiting toxicity of REOLYSIN in combination with pembrolizumab (KEYTRUDA®) and chemotherapy in patients with advanced or metastatic pancreatic adenocarcinoma who have failed, or did not tolerate, first line treatment.

In March 16, 2017 Oncolytics announced that cancer charity Myeloma UK launched MUK eleven, a phase 1b trial studying REOLYSIN in combination with Celgene Corporation's immunomodulatory drugs (IMiDs), Imnovid® (pomalidomide) or Revlimid® (lenalidomide), as a rescue treatment in relapsing myeloma patients. The first patient was treated in September 2017.

Oncolytics is conducting two phase 2 clinical trials studying REOLYSIN in pancreatic cancer: in collaboration with the University of Texas, Oncolytics is studying REOLYSIN in combination with gemcitabine (Gemzar®) in patients with advanced pancreatic cancer, and in collaboration with the NCI, Oncolytics is studying REOLYSIN in combination with carboplatin and paclitaxel as a first line treatment of patients with recurrent or metastatic pancreatic cancer.

See also

References

  1. ↑ 1.0 1.1 "What is Reolysin®? | Oncolytics Biotech Inc." (in en-US). Oncolytics Biotech Inc.. http://www.oncolyticsbiotech.com/reolysin/what-is-reolysin/. 
  2. ↑ 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. 
  3. ↑ 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. PMID 19594950. 
  4. ↑ 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. 
  5. ↑ Pandha, HS; Heinemann, L; Simpson, GR; Melcher, A; Prestwich, R; Errington, F; Coffey, M; Harrington, KJ et al. (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. 
  6. ↑ 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. PMID 20484020. 
  7. ↑ 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. 
  8. ↑ 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. PMID 19147761. 
  9. ↑ 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
  10. ↑ Oncolytics Biotech (ONCY) Announces Receipt of FDA Orphan Drug Designation for REOLYSIN. April 2015
  11. ↑ "Oncolytics Biotech® Inc. Announces FDA Fast Track Designation for REOLYSIN® in Metastatic Breast Cancer" (in en). http://www.newswire.ca/news-releases/oncolytics-biotech-inc-announces-fda-fast-track-designation-for-reolysin-in-metastatic-breast-cancer-621597233.html. 
  12. ↑ "Intellectual Property | Reolysin® | Oncolytics Biotech Inc." (in en-US). Oncolytics Biotech Inc.. http://www.oncolyticsbiotech.com/reolysin/intellectual-property/. 
  13. ↑ 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
  14. ↑ 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. 
  15. ↑ Thirukkumaran, C; Morris, DG (2009). "Oncolytic viral therapy using reovirus". Methods in Molecular Biology. Methods in Molecular Biology 542: 607–34. doi:10.1007/978-1-59745-561-9_31. ISBN 978-1-934115-85-5. PMID 19565924. 
  16. ↑ 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. PMID 214572. 
  17. ↑ 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. 
  18. ↑ 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. PMID 9628872. 
  19. ↑ 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. PMID 18483263. 
  20. ↑ Bos, JL (1989). "Ras oncogenes in human cancer: a review". Cancer Research 49 (17): 4682–9. PMID 2547513. 
  21. ↑ 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. 
  22. ↑ 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. 
  23. ↑ "Search of: reolysin - List Results - ClinicalTrials.gov" (in en). https://clinicaltrials.gov/ct2/results?cond=&term=reolysin&cntry1=&state1=&recrs=. 
  24. ↑ "Clinical Trials | Reolysin® | Oncolytics Biotech Inc." (in en-US). Oncolytics Biotech Inc.. http://www.oncolyticsbiotech.com/reolysin/clinical-trials/. 

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