High titer oncolytic measles virus production process by integration of dielectric spectroscopy as online monitoring system
Tanja A. Grein
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorDaniel Loewe
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorHauke Dieken
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorDenise Salzig
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorTobias Weidner
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorCorresponding Author
Peter Czermak
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Faculty of Biology and Chemistry, Justus Liebig University, Giessen, Germany
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group Bioresources, Giessen, Germany
Correspondence
Peter Czermak, University of Applied Sciences Mittelhessen, Wiesenstrasse 14, 35390 Giessen, Germany.
Email: peter.czermak@lse.thm.de
Search for more papers by this authorTanja A. Grein
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorDaniel Loewe
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorHauke Dieken
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorDenise Salzig
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorTobias Weidner
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Search for more papers by this authorCorresponding Author
Peter Czermak
Institute of Bioprocess Engineering Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
Faculty of Biology and Chemistry, Justus Liebig University, Giessen, Germany
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group Bioresources, Giessen, Germany
Correspondence
Peter Czermak, University of Applied Sciences Mittelhessen, Wiesenstrasse 14, 35390 Giessen, Germany.
Email: peter.czermak@lse.thm.de
Search for more papers by this authorAbstract
Oncolytic viruses offer new hope to millions of patients with incurable cancer. One promising class of oncolytic viruses is Measles virus, but its broad administration to cancer patients is currently hampered by the inability to produce the large amounts of virus needed for treatment (1010–1012 virus particles per dose). Measles virus is unstable, leading to very low virus titers during production. The time of infection and time of harvest are therefore critical parameters in a Measles virus production process, and their optimization requires an accurate online monitoring system. We integrated a probe based on dielectric spectroscopy (DS) into a stirred tank reactor to characterize the Measles virus production process in adherent growing Vero cells. We found that DS could be used to monitor cell adhesion on the microcarrier and that the optimal virus harvest time correlated with the global maximum permittivity signal. In 16 independent bioreactor runs, the maximum Measles virus titer was achieved approximately 40 hr after the permittivity maximum. Compared to an uncontrolled Measles virus production process, the integration of DS increased the maximum virus concentration by more than three orders of magnitude. This was sufficient to achieve an active Measles virus concentration of > 1010 TCID50 ml−1.
REFERENCES
- Anh-Nguyen, T., Tiberius, B., Pliquett, U., & Urban, G. A. (2016). An impedance biosensor for monitoring cancer cell attachment, spreading and drug-induced apoptosis. Sensors and Actuators A: Physical, 241, 231–237.
- Asami, K., Gheorghiu, E., & Yonezawa, T. (1999). Real-Time monitoring of yeast cell division by dielectric spectroscopy. Biophysical Journal, 76(6), 3345–3348.
- Betáková, T., Svetlílová, D., & Gocník, M. (2013). Overview of measles and mumps vaccine: Origin, present, and future of vaccine production. Acta Virologica, 57(2), 91–96.
-
Bluming, A., &
Ziegler, J.
(1971). Regression of Burkitt's lymphoma in association with measles infection.
The Lancet,
298(7715), 105–106.
10.1016/S0140-6736(71)92086-1 Google Scholar
- Devaux, P., von Messling, V., Songsungthong, W., Springfeld, C., & Cattaneo, R. (2007). Tyrosine 110 in the measles virus phosphoprotein is required to block STAT1 phosphorylation. Virology, 360(1), 72–83.
- Downey, B. J., Graham, L. J., Breit, J. F., & Glutting, N. K. (2014). A novel approach for using dielectric spectroscopy to predict viable cell volume (VCV) in early process development. Biotechnology Progress, 30(2), 479–487.
- Druzinec, D., Salzig, D., Brix, A., Kraume, M., Vilcinskas, A., Kollewe, C., & Czermak, P. (2013). Optimization of insect cell based protein production processes − online monitoring, expression systems, scale up. Advances in Biochemical Engineering/Biotechnology, 163, 65–100.
- Ducommun, P., Kadouri, A., von Stockar, U., & Marison, I. W. (2002). On-line determination of animal cell concentration in two industrial high-density culture processes by dielectric spectroscopy. Biotechnology and Bioengineering, 77(3), 316–323.
- EMA. (2015). First oncolytic immunotherapy medicine recommended for approval. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/10/news_detail_002421.jsp&mid=WC0b01ac058004d5c1.
- Emma, P., & Kamen, A. (2012). Real-time monitoring of influenza virus production kinetics in HEK293 cell cultures. Biotechnology Progress, 29(1), 275–284.
- FDA. (2015). FDA approves first-of-its-kind product for the treatment of melanoma. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm.
- Grein, T., Michalsky, R., & Czermak, P. (2014). Virus separation using membranes. Methods in Molecular Biology, 1104, 459–491.
- Grein, T. A., Schwebel, F., Kress, M., Loewe, D., Dieken, H., Salzig, D., … Czermak, P. (2017). Screening different host cell lines for the dynamic production of measles virus. Biotechnology Progress, 33(4), 989–997.
-
Grein, T. A.,
Weidner, T., &
Czermak, P.,
(2017). Concepts for the production of viruses and viral vectors in cell cultures. In S. J. T. Gowder (Ed.),
New Insights into Cell Culture Technology.
Rijeka:
InTech, p Ch. 06.
10.5772/66903 Google Scholar
- Huang, Y., Holzel, R., Pethig, R., & Xiao, B. W. (1992). Differences in the AC electrodynamics of viable and non-viable yeast cells determined through combined dielectrophoresis and electrorotation studies. Physics in Medicine and Biology, 37(7), 1499.
- Justice, C., Brix, A., Freimark, D., Kraume, M., Pfromm, P., Eichenmueller, B., & Czermak, P. (2011). Process control in cell culture technology using dielectric spectroscopy. Biotechnology Advances, 29(4), 391–401.
-
Kärber, G.
(1931). Beitrag zur kollektiven behandlung pharmakologischer reihenversuche.
Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie,
162(4), 480–483.
10.1007/BF01863914 Google Scholar
- Ludlow, M., Lemon, K., de Vries, R. D., McQuaid, S., Millar, E. L., van Amerongen, G., … Duprex, W. P. (2013). Measles virus infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial immune cells. Journal of Virology, 87(7), 4033–4042.
- Markx, G. H., & Davey, C. L. (1999). The dielectric properties of biological cells at radiofrequencies: Applications in biotechnology. Enzyme and Microbial Technology, 25(3-5), 161–171.
- Mendonca, R., Vaz-de-Lima, L., Oliveira, M., Pereira, C., & Hoshino-Shimizu, S. (1994). Studies on the efficiency of measles virus antigen production using VERO cell culture in a microcarrier system. Brazilian Journal of Medical and Biological Research, 27(7), 1575–1587.
- Mendonça, R. Z., Arrózio, S. J., Antoniazzi, M. M., Ferreira, J. M. C., & Pereira, C. A. (2002). Metabolic active-high density VERO cell cultures on microcarriers following apoptosis prevention by galactose/glutamine feeding. Journal of Biotechnology, 97(1), 13–22.
- Negrete, A., Esteban, G., & Kotin, R. M. (2007). Process optimization of large-scale production of recombinant adeno-associated vectors using dielectric spectroscopy. Applied Microbiology and Biotechnology, 76(4), 761–772.
- Pesonen, S., Helin, H., Nokisalmi, P., Escutenaire, S., Ribacka, C., Sarkioja, M., … Laasonen, L. (2010). Oncolytic adenovirus treatment of a patient with refractory neuroblastoma. Acta Oncologica, 49, 120–122.
- Petiot, E., Guedon, E., Blanchard, F., Gény, C., Pinton, H., & Marc, A. (2010). Kinetic characterization of vero cell metabolism in a serum-free batch culture process. Biotechnology and Bioengineering, 107(1), 143–153.
- Power, A. T., & Bell, J. C. (2008). Taming the Trojan horse: Optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy. Gene Therapy, 15(10), 772–779.
-
Reed, L. J., &
Muench, H.
(1938). A simple method of estimating fifty per cent endpoints.
American Journal of Epidemiology,
27(3), 493–497.
10.1093/oxfordjournals.aje.a118408 Google Scholar
- Rentier, B., Hooghe-Peters, E. L., & Dubois-Dalcq, M. (1978). Electron microscopic study of measles virus infection: Cell fusion and hemadsorption. Journal of Virology, 28(2), 567–577.
- Russell, S. J., Federspiel, M. J., Peng, K.-W., Tong, C., Dingli, D., Morice, W. G., & Leung, N., et al. (2014). Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clinic Proceedings, 89(7), 926–933.
- Schwan, H. P. (1957). Electrical properties of tissue and cell suspensions. Advances in Biological and Medical Physics, 5, 147–209.
- Scott, J. V., & Choppin, P. W. (1982). Enhanced yields of measles virus from cultured cells. Journal of Virological Methods, 5(3), 173–179.
- Singh, P., Doley, J., Kumar, G., Sahoo, A., & Tiwari, A. (2012). Oncolytic viruses & their specific targeting to tumour cells. 571–584.
- Sviben, D., Forčić, D., Kurtović, T., Halassy, B., & Brgles, M. (2016). Stability, biophysical properties and effect of ultracentrifugation and diafiltration on measles virus and mumps virus. Archives of Virology, 161(6), 1455–1467.
-
Thirukkumaran, C., &
Morris, D. G.,
(2015). Oncolytic viral therapy using reovirus. In: In W. Walther & U. Stein (Eds.),
gene therapy of solid cancers: Methods and protocols. (pp. 187–223).
New York, NY:
Springer New York.
10.1007/978-1-4939-2727-2_12 Google Scholar
- Toyoda, H., Yin, J., Mueller, S., Wimmer, E., & Cello, J. (2007). Oncolytic treatment and cure of neuroblastoma by a novel attenuated poliovirus in a novel poliovirus-susceptible animal model. Cancer Research, 67(6), 2857–2864.
- Trabelsi, K., Majoul, S., Rourou, S., & Kallel, H. (2014). Development of a measles vaccine production process in MRC-5 cells grown on Cytodex1 microcarriers and in a stirred bioreactor. Applied Microbiology and Biotechnology, 93(3), 1031–1040.
- Vidal, L., Pandha, H. S., Yap, T. A., White, C. L., Twigger, K., Vile, R. G., … DeBono, J. S. (2008). A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer. Clin Cancer Research, 14(21), 7127–7137.
- Wang, M., Libbey, J. E., Tsunoda, I., & Fujinami, R. S. (2003). Modulation of immune system function by measles virus infection. II. Infection of B Cells Leads to the Production of a Soluble Factor That Arrests Uninfected B Cells in G0/G1. Viral Immunology, 16(1), 45–55.
- Weber, C., Gokorsch, S., & Czermak, P. (2007). Expansion and chondrogenic differentiation of human mesenchymal stem cells. The International Journal of Artificial Organs, 30(7), 611–618.
- Weiss, K., Gerstenberger, J., Salzig, D., Mühlebach, M. D., Cichutek, K., Pörtner, R., & Czermak, P. (2015). Oncolytic measles viruses produced at different scales under serum-free conditions. Engineering in Life Sciences, 15(4), 425–436.
- Weiss, K., Salzig, D., Mühlebach, M., Cichutek, K., Pörtner, R., & Czermak, P. (2012). Key parameters of measles virus production for oncolytic virotherapy. American Journal of Biochemistry and Biotechnology, 8(2), 81–98.
-
Weiss, K.,
Salzig, D.,
Röder, Y.,
Gerstenberger, J.,
Mühlebach, M. D.,
Cichutek, K., …
Czermak, P.
(2013). Influence of process conditions on measles virus stability.
American J Biochem Biotechnol,
3(9), 243–254.
10.3844/ajbbsp.2013.243.254 Google Scholar
- Wollmann, G., Ozduman, K., & van den Pol, A. N. (2012). Oncolytic virus therapy for glioblastoma multiforme: Concepts and candidates. The Cancer Journal, 18(1), 69–81.
- Zhao, Y., Liu, Q., Sun, H., Chen, D., Li, Z., Fan, B., … Xue, C. (2016). Electrical Property Characterization of Neural Stem Cells in Differentiation. PLoS ONE 11(6), 0158044.
Citing Literature
Metrics
Details
© 2017 Wiley Periodicals, Inc.
Research funding
- Bundesministerium für Bildung und Forschung. Grant Number: 03FH001IX5
- Hessisches Ministerium für Wissenschaft und Kunst. Grant Number: LOEWE Center for Insect Biotechnology and Bioresources
Keywords
Publication History
- 25 March 2018
- 04 February 2018
- 30 December 2017
- 26 December 2017
- 30 November 2017
- 01 September 2017
