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Pelareorep

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Pelareorep (previously known under the trademark Reolysin)[1] is a proprietary isolate of the unmodified human reovirus being developed as a systemically administered immuno-oncological viral agent for the treatment of solid tumors and hematological malignancies.[2][3] Pelareorep is an oncolytic virus, which means that it preferentially lyses cancer cells. Pelareorep also promotes an inflamed tumor phenotype through innate and adaptive immune responses.[2] Preliminary clinical trials indicate that it may have anti-cancer effects 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.[4][5][6][7][8][9][10]

In April 2015, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to pelareorep for malignant glioma.[11] In May 2017, the FDA granted Fast Track Designation for pelareorep in metastatic breast cancer.[12]

Oncolytics Biotech has more than 415 patents for pelareorep issued globally, including more than 60 in the U.S. and 20 in Canada, as well as numerous patents pending worldwide.[13]

Mechanism of action

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Reovirus, an acronym for Respiratory Enteric Orphan virus, generally infects mammalian respiratory and bowel systems.[14] Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms.[15]

Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it reproduces well in certain cancer cell lines.[16][17][18] 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.[19] 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.[20] 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 pelareorep may be an effective therapeutic for many Ras-activated tumor types and potentially for some cell proliferative disorders.[21][22][23]

In both single-arm and randomized phase 2 clinical studies, pelareorep, 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 pelareorep 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

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Pelareorep has been evaluated in numerous clinical trials in variety of cancers, including pancreatic, breast, head and neck, prostate, lung, colorectal, bladder and ovarian cancers.[24]

Pelareorep clinical development plan is based on drug combinations that can potentially boost each response of pelareorep'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).[25]

As part of pelareorep'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 pelareorep for the treatment of metastatic breast cancer, and in September 2017, the company announced a successful End-of-Phase 2 meeting with the FDA.[citation needed]

Oncolytics is conducting its first study of pelareorep in combination with a checkpoint inhibitors in an open-label phase 1b trial. The trial will assess the safety and dose-limiting toxicity of pelareorep 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.[citation needed]

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

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

See also

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References

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  1. ^ "Oncolytics Biotech Announces Publication of Positive Clinical Results for Pelareorep in Abstract for ESMO 2018 Congress". Oncolytics Biotech. October 11, 2018.
  2. ^ a b "What is Reolysin? | Oncolytics Biotech Inc". Oncolytics Biotech Inc. Archived from the original on 2017-10-26. Retrieved 2017-11-07.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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 3907942. PMID 20484020.
  8. ^ 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. S2CID 8565408.
  9. ^ 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 3046733. PMID 19147761.
  10. ^ 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[usurped]
  11. ^ Oncolytics Biotech (ONCY) Announces Receipt of FDA Orphan Drug Designation for REOLYSIN. April 2015
  12. ^ "Oncolytics Biotech Inc. Announces FDA Fast Track Designation for REOLYSIN in Metastatic Breast Cancer". www.newswire.ca. Retrieved 2017-11-07.
  13. ^ "Intellectual Property | Reolysin | Oncolytics Biotech Inc". Oncolytics Biotech Inc. Retrieved 2017-11-07.
  14. ^ 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
  15. ^ 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. S2CID 13547783.
  16. ^ Thirukkumaran, C; Morris, DG (2009). "Oncolytic Viral Therapy Using Reovirus". Gene Therapy of Cancer. Methods in Molecular Biology. Vol. 542. pp. 607–34. doi:10.1007/978-1-59745-561-9_31. ISBN 978-1-934115-85-5. PMID 19565924.
  17. ^ 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. doi:10.1128/jvi.28.2.444-449.1978. PMC 354293. PMID 214572.
  18. ^ 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. S2CID 36721884.
  19. ^ 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.
  20. ^ 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.
  21. ^ Bos, JL (1989). "Ras oncogenes in human cancer: a review". Cancer Research. 49 (17): 4682–9. PMID 2547513.
  22. ^ 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.
  23. ^ 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.
  24. ^ "Search of: reolysin - List Results - ClinicalTrials.gov". Retrieved 2017-11-07.
  25. ^ "Clinical Trials | Reolysin | Oncolytics Biotech Inc". Oncolytics Biotech Inc. Archived from the original on 2017-10-26. Retrieved 2017-11-07.
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