1887

Abstract

Oncolytic virotherapy is an emerging treatment option for numerous cancers, with several virus families currently being evaluated in clinical trials. More specifically, vaccine-strain measles virus has arisen as a promising candidate for the treatment of different tumour types in several early clinical trials. Replicating viruses, and especially RNA viruses without proofreading polymerases, can rapidly adapt to varying environments by selecting quasispecies with advantageous genetic mutations. Subsequently, these genetic alterations could potentially weaken the safety profile of virotherapy. In this study, we demonstrate that, following an extended period of virus replication in producer or cancer cell lines, the quasispecies consensus sequence of vaccine strain-derived measles virus accrues a remarkably small number of mutations throughout the nonsegmented negative-stranded RNA genome. Interestingly, we detected a nonrandom distribution of genetic alterations within the genome, with an overall decreasing frequency of mutations from the 3′ genome start to its 5′ end. Comparing the serially passaged viruses to the parental virus on producer cells, we found that the acquired consensus mutations did not drastically change viral replication kinetics or cytolytic potency. Collectively, our data corroborate the genomic stability and excellent safety profile of oncolytic measles virus, thus supporting its continued development and clinical translation as a promising viro-immunotherapeutic.

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2020-02-13
2020-02-23
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References

  1. Aref S, Bailey K, Fielding A. Measles to the rescue: a review of oncolytic measles virus. Viruses 2016;8:294 [CrossRef]
    [Google Scholar]
  2. Bellini WJ, Rota JS, Rota PA. Virology of measles virus. J Infect Dis 1994;170:S15–S23 [CrossRef]
    [Google Scholar]
  3. Daikoku E, Morita C, Kohno T, Sano K. Analysis of morphology and infectivity of measles virus particles. Bulletin of the Osaka Medical College 2007;53:107–114
    [Google Scholar]
  4. Cattaneo R, Donohue RC, Generous AR, Navaratnarajah CK, Pfaller CK. Stronger together: Multi-genome transmission of measles virus. Virus Res 2019;265:74–79 [CrossRef]
    [Google Scholar]
  5. Rima BK, Duprex WP. The measles virus replication cycle. Curr Top Microbiol Immunol 2009;329:77–102
    [Google Scholar]
  6. Noyce RS, Bondre DG, Ha MN, Lin L-T, Sisson G et al. Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoS Pathog 2011;7:e1002240 [CrossRef]
    [Google Scholar]
  7. Mühlebach MD, Mateo M, Sinn PL, Prüfer S, Uhlig KM et al. Adherens junction protein Nectin-4 is the epithelial receptor for measles virus. Nature 2011;480:530–533 [CrossRef]
    [Google Scholar]
  8. Tatsuo H, Ono N, Tanaka K, Yanagi Y. Slam (CDw150) is a cellular receptor for measles virus. Nature 2000;406:893–897 [CrossRef]
    [Google Scholar]
  9. Mateo M, Navaratnarajah CK, Cattaneo R. Structural basis of efficient contagion: measles variations on a theme by parainfluenza viruses. Curr Opin Virol 2014;5:16–23 [CrossRef]
    [Google Scholar]
  10. Griffin DE, Lin W-H, Pan C-H. Measles virus, immune control, and persistence. FEMS Microbiol Rev 2012;36:649–662 [CrossRef]
    [Google Scholar]
  11. World Health Organization Measles. 2019
  12. The Lancet Measles eradication: a goal within reach, slipping away. The Lancet 2019;393:1669 [CrossRef]
    [Google Scholar]
  13. Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L et al. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol 2019;4:eaay6125 [CrossRef]
    [Google Scholar]
  14. Mina MJ, Kula T, Leng Y, Li M, de Vries RD et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science 2019;366:599–606 [CrossRef]
    [Google Scholar]
  15. Pol JG, Lévesque S, Workenhe ST, Gujar S, Le Boeuf F et al. Trial Watch: oncolytic viro-immunotherapy of hematologic and solid tumors. Oncoimmunology 2018;7:e1503032 [CrossRef]
    [Google Scholar]
  16. Ungerechts G, Springfeld C, Frenzke ME, Lampe J, Johnston PB et al. Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res 2007;67:10939–10947 [CrossRef]
    [Google Scholar]
  17. Engeland CE, Grossardt C, Veinalde R, Bossow S, Lutz D et al. Ctla-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Molecular Therapy 2014;22:1949–1959 [CrossRef]
    [Google Scholar]
  18. Li H, Peng K-W, Dingli D, Kratzke RA, Russell SJ. Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy. Cancer Gene Ther 2010;17:550–558 [CrossRef]
    [Google Scholar]
  19. Veinalde R, Grossardt C, Hartmann L, Bourgeois-Daigneault M-C, Bell JC et al. Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation. Oncoimmunology 2017;6:e1285992 [CrossRef]
    [Google Scholar]
  20. Speck T, Heidbuechel JPW, Veinalde R, Jaeger D, von Kalle C et al. Targeted bite expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clin Cancer Res 2018;24:2128–2137 [CrossRef]
    [Google Scholar]
  21. Maurer S, Salih H, Smirnow I, Lauer U, Berchtold S. Suicide gene‑armed measles vaccine virus for the treatment of AML. Int J Oncol 2019; [CrossRef]
    [Google Scholar]
  22. Hudacek AW, Navaratnarajah CK, Cattaneo R. Development of measles virus-based shielded oncolytic vectors: suitability of other paramyxovirus glycoproteins. Cancer Gene Ther 2013;20:109–116 [CrossRef]
    [Google Scholar]
  23. Miest TS, Yaiw K-C, Frenzke M, Lampe J, Hudacek AW et al. Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis. Molecular Therapy 2011;19:1813–1820 [CrossRef]
    [Google Scholar]
  24. Muñoz-Alía MA, Russell SJ. Probing morbillivirus antisera neutralization using functional chimerism between measles virus and canine distemper virus envelope glycoproteins. Viruses 2019;11:688 [CrossRef]
    [Google Scholar]
  25. Kaufmann JK, Bossow S, Grossardt C, Sawall S, Kupsch J et al. Chemovirotherapy of malignant melanoma with a targeted and armed oncolytic measles virus. J Invest Dermatol 2013;133:1034–1042 [CrossRef]
    [Google Scholar]
  26. Friedrich K, Hanauer JRH, Prüfer S, Münch RC, Völker I et al. DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety. Molecular Therapy 2013;21:849–859 [CrossRef]
    [Google Scholar]
  27. Bach P, Abel T, Hoffmann C, Gal Z, Braun G et al. Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Res 2013;73:865–874 [CrossRef]
    [Google Scholar]
  28. Nakamura T, Peng K-W, Harvey M, Greiner S, Lorimer IAJ et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nat Biotechnol 2005;23:209–214 [CrossRef]
    [Google Scholar]
  29. Leber MF, Bossow S, Leonard VHJ, Zaoui K, Grossardt C et al. MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Molecular Therapy 2011;19:1097–1106 [CrossRef]
    [Google Scholar]
  30. Baertsch MA, Leber MF, Bossow S, Singh M, Engeland CE et al. Microrna-Mediated multi-tissue detargeting of oncolytic measles virus. Cancer Gene Ther 2014;21:373–380 [CrossRef]
    [Google Scholar]
  31. Ketzer P, Kaufmann JK, Engelhardt S, Bossow S, von Kalle C et al. Artificial riboswitches for gene expression and replication control of DNA and RNA viruses. Proc Natl Acad Sci U S A 2014;111:E554–E562 [CrossRef]
    [Google Scholar]
  32. Galanis E, Atherton PJ, Maurer MJ, Knutson KL, Dowdy SC et al. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 2015;75:22–30 [CrossRef]
    [Google Scholar]
  33. Russell SJ, Federspiel MJ, Peng K-W, Tong C, Dingli D et al. Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clinic Proceedings 2014;89:926–933 [CrossRef]
    [Google Scholar]
  34. Galanis E, Hartmann LC, Cliby WA, Long HJ, Peethambaram PP et al. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res 2010;70:875–882 [CrossRef]
    [Google Scholar]
  35. Domingo E, Escarmís C, Sevilla N, Moya A, Elena SF et al. Basic concepts in RNA virus evolution. Faseb J 1996;10:859–864 [CrossRef]
    [Google Scholar]
  36. Domingo E, Holland JJ. Rna virus mutations and fitness for survival. Annu Rev Microbiol 1997;51:151–178 [CrossRef]
    [Google Scholar]
  37. Shirogane Y, Watanabe S, Yanagi Y. Cooperation between different variants: a unique potential for virus evolution. Virus Res 2019;264:68–73 [CrossRef]
    [Google Scholar]
  38. Martin A, Staeheli P, Schneider U. Rna polymerase II-controlled expression of antigenomic RNA enhances the rescue efficacies of two different members of the Mononegavirales independently of the site of viral genome replication. J Virol 2006;80:5708–5715 [CrossRef]
    [Google Scholar]
  39. Calain P, Roux L. The rule of six, a basic feature for efficient replication of Sendai virus defective interfering RNA. J Virol 1993;67:4822–4830 [CrossRef]
    [Google Scholar]
  40. Kolakofsky D, Pelet T, Garcin D, Hausmann Stéphane, Curran J et al. Paramyxovirus RNA synthesis and the requirement for hexamer genome length: the rule of six revisited. J Virol 1998;72:891–899 [CrossRef]
    [Google Scholar]
  41. Radecke F, Spielhofer P, Schneider H, Kaelin K, Huber M et al. Rescue of measles viruses from cloned DNA. Embo J 1995;14:5773–5784 [CrossRef]
    [Google Scholar]
  42. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9:676–682 [CrossRef]
    [Google Scholar]
  43. Bossow S, Grossardt C, Temme A, Leber MF, Sawall S et al. Armed and targeted measles virus for chemovirotherapy of pancreatic cancer. Cancer Gene Ther 2011;18:598–608 [CrossRef]
    [Google Scholar]
  44. Zaoui K, Bossow S, Grossardt C, Leber MF, Springfeld C et al. Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus. Cancer Gene Ther 2012;19:181–191 [CrossRef]
    [Google Scholar]
  45. Vitale G, van Eijck CH, van Koetsveld Ing PM, Erdmann JI, Speel EJ et al. Type I interferons in the treatment of pancreatic cancer: mechanisms of action and role of related receptors. Ann Surg 2007;246:259–268
    [Google Scholar]
  46. Potapov V, Ong JL. Examining sources of error in PCR by single-molecule sequencing. PLoS One 2017;12:e0169774 [CrossRef]
    [Google Scholar]
  47. Lyons DM, Lauring AS. Evidence for the selective basis of Transition-to-Transversion substitution bias in two RNA viruses. Mol Biol Evol 2017;34:3205–3215 [CrossRef]
    [Google Scholar]
  48. Acevedo A, Brodsky L, Andino R. Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature 2014;505:686–690 [CrossRef]
    [Google Scholar]
  49. Toth AM, Zhang P, Das S, George CX, Samuel CE. Interferon action and the double-stranded RNA-dependent enzymes ADAR1 adenosine deaminase and PKR protein kinase. Prog Nucleic Acid Res Mol Biol 2006;81:369–434
    [Google Scholar]
  50. Cattaneo R, Schmid A, Eschle D, Baczko K, ter Meulen V et al. Biased hypermutation and other genetic changes in defective measles viruses in human brain infections. Cell 1988;55:255–265 [CrossRef]
    [Google Scholar]
  51. Toth AM, Devaux P, Cattaneo R, Samuel CE. Protein kinase PKR mediates the apoptosis induction and growth restriction phenotypes of C protein-deficient measles virus. J Virol 2009;83:961–968 [CrossRef]
    [Google Scholar]
  52. Pfaller CK, Donohue RC, Nersisyan S, Brodsky L, Cattaneo R. Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the proviral activity of ADAR1p150. PLoS Biol 2018;16:e2006577 [CrossRef]
    [Google Scholar]
  53. Ward SV, George CX, Welch MJ, Liou L-Y, Hahm B et al. Rna editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci U S A 2011;108:331–336 [CrossRef]
    [Google Scholar]
  54. George CX, John L, Samuel CE, Editor ARNA. An RNA editor, adenosine deaminase acting on double-stranded RNA (ADAR1). J Interferon Cytokine Res 2014;34:437–446 [CrossRef]
    [Google Scholar]
  55. Fulton BO, Sachs D, Beaty SM, Won ST, Lee B et al. Mutational analysis of measles virus suggests constraints on antigenic variation of the glycoproteins. Cell Rep 2015;11:1331–1338 [CrossRef]
    [Google Scholar]
  56. Bromham L, Penny D. The modern molecular clock. Nat Rev Genet 2003;4:216–224 [CrossRef]
    [Google Scholar]
  57. Kumar S. Molecular clocks: four decades of evolution. Nat Rev Genet 2005;6:654–662 [CrossRef]
    [Google Scholar]
  58. Schrag SJ, Rota PA, Bellini WJ. Spontaneous mutation rate of measles virus: direct estimation based on mutations conferring monoclonal antibody resistance. J Virol 1999;73:51–54 [CrossRef]
    [Google Scholar]
  59. Zhang X, Rennick LJ, Duprex WP, Rima BK. Determination of spontaneous mutation frequencies in measles virus under nonselective conditions. J Virol 2013;87:2686–2692 [CrossRef]
    [Google Scholar]
  60. Yan W, Kitzes G, Dormishian F, Hawkins L, Sampson-Johannes A et al. Developing novel oncolytic adenoviruses through Bioselection. J Virol 2003;77:2640–2650 [CrossRef]
    [Google Scholar]
  61. Kuhn I, Harden P, Bauzon M, Chartier C, Nye J et al. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer. PLoS One 2008;3:e2409 [CrossRef]
    [Google Scholar]
  62. Garijo R, Hernández-Alonso P, Rivas C, Diallo J-S, Sanjuán R. Experimental evolution of an oncolytic vesicular stomatitis virus with increased selectivity for p53-deficient cells. PLoS One 2014;9:e102365 [CrossRef]
    [Google Scholar]
  63. Gao Y, Whitaker-Dowling P, Watkins SC, Griffin JA, Bergman I. Rapid adaptation of a recombinant vesicular stomatitis virus to a targeted cell line. J Virol 2006;80:8603–8612 [CrossRef]
    [Google Scholar]
  64. Bauzon M, Hermiston TW. Oncolytic viruses: the power of directed evolution. Adv Virol 2012;2012:5863895 [CrossRef]
    [Google Scholar]
  65. Lauring AS, Jones JO, Andino R. Rationalizing the development of live attenuated virus vaccines. Nat Biotechnol 2010;28:573–579 [CrossRef]
    [Google Scholar]
  66. Enders JF, Katz SL, Milovanovic MV, Holloway A. Studies on an attenuated measles-virus vaccine. I. development and preparations of the vaccine: technics for assay of effects of vaccination. N Engl J Med 1960;263:153–159
    [Google Scholar]
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