Virotherapy 

Overview

The development and characterization of recombinant negative-strand RNA vectors is an established area of research that covers aspects of basic vector biology, vector preparation, regulation of foreign gene expression, design and generation of new vectors with deletions or mutations of viral genes, modulation of vector tropism, characterization of transgene expression in vivo, development of vector application and reapplication protocols, duration of gene expression and genetic stability of vectors, including vaccine-based measles virus (MV) vectors.

The Virotherapy group has developed an alternative targeting system for MV that is based on cleavage activation of the viral F protein by matrix metalloproteases that are present on tumor cells. The group has also characterized the first MV-encoding suicide genes, including the herpes simplex virus thymidine kinase, the Escherichia coli cytosine deaminase and the E. coli purine nucleoside phosphorylase. The group has established the first immunocompetent model of MV oncolysis that can now be used to investigate the influence of the immune system on MV oncolysis and on engineered MV-encoding immunostimulatory genes, or chimeric MV. Finally, the group has engineered chimeric viruses displaying glycoproteins from other paramyxoviridae that can evade pre-existing MV antibodies.

Significant accomplishments of the past 5 years

The Virotherapy group has:

• shown that a targeted and convertase-armed MV can synergize with fludarabine, thereby improving the safety and efficacy of MV vectors (Cancer Res 2007, 67:10939-47).
• developed the first immunocompetent murine model for MV oncolysis studies, which allowed the group to determine the influence of the immune system on MV oncolysis and on engineered MV-encoding immunostimulatory genes, or chimeric MV (Mol Ther 2007, 15:1991-7).
• demonstrated the oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases; this work defines another level of specificity (Cancer Res 2006, 66:7694-700).
• developed a mantle cell lymphoma salvage regimen based on synergy between a reprogrammed oncolytic virus and two chemotherapeutics; this is an example of how the gap between bench and bedside can be bridged (Gene Ther 2010, 17:1506-16)
  

5 most significant publications of the past 5 years

Armeanu S, Bitzer M, Smirnow I, Bossow S, Appel S, Ungerechts G, Bernloehr C, Neubert WJ, Lauer UM, Brossart P: Severe impairment of dendritic cell allostimulatory activity by Sendai virus vectors is overcome by matrix protein gene deletion. J Immunol 2005, 175:4971-80

Springfeld C, von Messling V, Frenzke M, Ungerechts G, Buchholz CJ, Cattaneo R: Oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases. Cancer Res 2006, 66:7694-700

Ungerechts G, Springfeld C, Frenzke M, Lampe J, Johnston P, Parker WB, Sorscher EJ, Cattaneo R: Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res 2007, 67:10939-47

Ungerechts G, Springfeld C, Frenzke ME, Lampe J, Parker WB, Sorscher EJ, Cattaneo R: An Immunocompetent Murine Model for Oncolysis with an Armed and Targeted Measles Virus. Mol Ther 2007, 15:1991-7

Ungerechts G, Frenzke ME, Yaiw KC, Miest T, Johnston PB, Cattaneo R. Mantle cell lymphoma salvage regimen: synergy between a reprogrammed oncolytic virus and two chemotherapeutics. Gene Ther. 2010;17(12):1506-16.

Contact

Dr. Dr. Guy Ungerechts
National Center of Tumor Diseases (NCT) Heidelberg and
German Cancer Research Center (DKFZ)
Max-Eder-Junior Research Group

Translational Oncology
Im Neuenheimer Feld 581, TP4
69120 Heidelberg

Tel: +496221421640
Fax: +49 6221 421611
guy.ungerechts@nct-heidelberg.de

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