Parvovirus H-1 an oncolytic virus undergoing clinical trials for pancreatic cancer

Parvovirus H-1 (H-1PV) was originally isolated (reported in 1960) from a number of transplantable human tumour cell lines including HEp 1 and is able to enter normal human cells [1] (figure 1). It is known to infect rats in the field. Its suitability as an oncolytic therapy is under investigation. The H-1PV cognate cellular receptor is unknown however sialic acid is important for cell membrane binding by the virus [2]. Due to its dependence on S phase factors only present during active cell replication and the activation of normal cell innate antiviral programs it is non-pathogenic [3]. Unlike viral vectors such as adenovirus the average person’s immune system has not encountered H-1PV before meaning that it could be suitable for systemic delivery [3]. In proliferative cancer cells H-1PV can replicate and is oncolytic primarily due to the viral protein NS1 [4]. One potential drawback of H-1PV is that due to its dependence on S phase factors it is reasonable to suspect it would not be effective against non-proliferative cancer stem cells unlike other oncolytic vectors such as adenovirus. However it has been shown in in vitro neurosphere cultures that it can infect and lyse brain tumour stem cells [5]. It remains to be seen whether it is as effective against cancer stem cells in vivo. New effective therapies for pancreatic cancer are required due to the dismal effectiveness of current drugs. Parvovirus H-1 is a potential next generation therapeutic currently under investigation for pancreatic cancer.

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Figure 1: 3-D molecular model of parvovirus. Colour scheme is arbitrary. Credit: AJC PHOTOGRAPHY. No changes were made. Creative Commons Attribution-ShareAlike 2.0.

It has been shown in mouse and rat xenograft models of pancreatic cancer that H-1PV synergises with gemcitabine treatment to improve overall survival time [6]. The H-1PV virus however has a dependence upon active SMAD4 expression for replication in pancreatic cancer cell lines [7]. SMAD4 tends to be lost in late stage metastatic pancreatic cancer which also tends to be the group of patients first tested with an investigational new drug. H-1PV is undergoing phase I and II clinical trials in metastatic pancreatic cancer [8]. It would be wise to confirm the SMAD4 status of the patients in these trials so that efficacy can be correlated with SMAD4 status. It would also be wise for future trials to select patients with a confirmed active SMAD4 tumour status.

Refs

  1. Toolan HW, Dalldore G, Barclay M, Chandra S, Moore AE. AN UNIDENTIFIED, FILTRABLE AGENT ISOLATED FROM TRANSPLANTED HUMAN TUMORS. Proceedings of the National Academy of Sciences of the United States of America. 1960;46(9):1256-1258. PMCID: PMC223034
  2. Marchini, Antonio, Serena Bonifati, Eleanor M Scott, Assia L Angelova, and Jean Rommelaere. ‘Oncolytic Parvoviruses: From Basic Virology to Clinical Applications’. Virology Journal 12, no. 1 (2015): 6. doi:10.1186/s12985-014-0223-y.
  3. Allaume, X., N. El-Andaloussi, B. Leuchs, S. Bonifati, A. Kulkarni, T. Marttila, J. K. Kaufmann, et al. ‘Retargeting of Rat Parvovirus H-1PV to Cancer Cells through Genetic Engineering of the Viral Capsid’. Journal of Virology 86, no. 7 (1 April 2012): 3452–65. doi:10.1128/JVI.06208-11.
  4. Hristov, G., M. Kramer, J. Li, N. El-Andaloussi, R. Mora, L. Daeffler, H. Zentgraf, J. Rommelaere, and A. Marchini. ‘Through Its Nonstructural Protein NS1, Parvovirus H-1 Induces Apoptosis via Accumulation of Reactive Oxygen Species’. Journal of Virology 84, no. 12 (15 June 2010): 5909–22. doi:10.1128/JVI.01797-09.
  5. Lacroix, J, R Josupeit, S Kern, C Herold-Mende, F Schlund, H Witt, T Milde, et al. ‘Parvovirus H-1 (H-1PV) exerts oncolytic effects in cell culture models of human brain tumor-initiating cells’. Klin Padiatr 224, no. 06 (9 November 2012): A9. doi:10.1055/s-0032-1320177.
  6. Angelova, A. L., M. Aprahamian, S. P. Grekova, A. Hajri, B. Leuchs, N. A. Giese, C. Dinsart, et al. ‘Improvement of Gemcitabine-Based Therapy of Pancreatic Carcinoma by Means of Oncolytic Parvovirus H-1PV’. Clinical Cancer Research 15, no. 2 (15 January 2009): 511–19. doi:10.1158/1078-0432.CCR-08-1088.
  7. Dempe, Sebastian, Alexandra Y. Stroh-Dege, Elisabeth Schwarz, Jean Rommelaere, and Christiane Dinsart. ‘SMAD4: A Predictive Marker of PDAC Cell Permissiveness for Oncolytic Infection with Parvovirus H-1PV’. International Journal of Cancer, 2010, NA – NA. doi:10.1002/ijc.24992.
  8. ‘Parvovirus H-1 (ParvOryx) in Patients With Metastatic Inoperable Pancreatic Cancer – Full Text View – ClinicalTrials.gov’. Accessed 29 February 2016. https://clinicaltrials.gov/ct2/show/NCT02653313?term=H%E2%80%901PV&rank=2.
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