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Pelareorep

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Pelareorep(previously known under the trademarkReolysin)[1]is a proprietary isolate of the unmodifiedhuman reovirusbeing developed as a systemically administeredimmuno-oncologicalviral agent for the treatment ofsolid tumorsandhematological malignancies.[2][3]Pelareorep is anoncolytic virus,which means that it preferentially lyses cancer cells. Pelareorep also promotes an inflamed tumor phenotype throughinnateandadaptive immuneresponses.[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, theU.S. Food and Drug Administration(FDA) grantedorphan drug designationto pelareorep formalignant glioma.[11]In May 2017, the FDA granted Fast Track Designation for pelareorep inmetastatic breast cancer.[12]

Oncolytics Biotechhas 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 activatedRas(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 ofchemokines/cytokinescausingnatural 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 educateT-cellsto 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 weeklypaclitaxeltherapy. 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 withpembrolizumab(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 MUKeleven,a phase 1b trial studying pelareorep in combination with Celgene Corporation's immunomodulatory drugs (IMiDs),pomalidomideorlenalidomide,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 withgemcitabinein patients with advanced pancreatic cancer, and in collaboration with the NCI, Oncolytics is studying pelareorep in combination withcarboplatinand 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. ^ab"What is Reolysin? | Oncolytics Biotech Inc".Oncolytics Biotech Inc.Archived fromthe originalon 2017-10-26.Retrieved2017-11-07.
  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.PMID19806501.
  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.PMC2723073.PMID19594950.
  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.PMID18245555.
  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.PMID19773377.
  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.PMC3907942.PMID20484020.
  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.PMID16543920.S2CID8565408.
  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.PMC3046733.PMID19147761.
  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.Retrieved2017-11-07.
  13. ^"Intellectual Property | Reolysin | Oncolytics Biotech Inc".Oncolytics Biotech Inc.Retrieved2017-11-07.
  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.PMID18323793.S2CID13547783.
  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.ISBN978-1-934115-85-5.PMID19565924.
  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.PMC354293.PMID214572.
  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.PMID562142.S2CID36721884.
  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.PMC1170673.PMID9628872.
  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.PMC2871708.PMID18483263.
  21. ^Bos, JL (1989). "Ras oncogenes in human cancer: a review".Cancer Research.49(17): 4682–9.PMID2547513.
  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.PMID14563121.
  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.PMID15970267.
  24. ^"Search of: reolysin - List Results - ClinicalTrials.gov".Retrieved2017-11-07.
  25. ^"Clinical Trials | Reolysin | Oncolytics Biotech Inc".Oncolytics Biotech Inc.Archived fromthe originalon 2017-10-26.Retrieved2017-11-07.
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