TY - JOUR
T1 - Virotherapy Research in Germany
T2 - From Engineering to Translation
AU - Ungerechts, Guy
AU - Engeland, Christine E.
AU - Buchholz, Christian J.
AU - Eberle, Jürgen
AU - Fechner, Henry
AU - Geletneky, Karsten
AU - Holm, Per Sonne
AU - Kreppel, Florian
AU - Kühnel, Florian
AU - Lang, Karl Sebastian
AU - Leber, Mathias F.
AU - Marchini, Antonio
AU - Moehler, Markus
AU - Mühlebach, Michael D.
AU - Rommelaere, Jean
AU - Springfeld, Christoph
AU - Lauer, Ulrich M.
AU - Nettelbeck, Dirk M.
N1 - Funding Information:
The Kreppel group has developed a combination of genetic and chemical viral capsid modification technologies.17,78 Using this ‘‘geneti-chemical’’ modification technology, the viral capsids can be modified precisely with shielding molecules, targeting moieties or a combination thereof. Importantly, the choice of molecules that can be coupled to shield the viral capsid from unwanted virus–host interactions and target it to cancer tissue is not restricted by the substance class: proteins up to 150 kDa in size, (nonnatural) peptides, carbohydrates, lipids, small molecules, and synthetic or natural polymers can be chemically attached to the virus surface with high efficiency and specificity in a way that maintains the virus’s oncolytic potency. Using mouse models and human blood, the group demonstrated that unwanted vector–host interactions such as neutralization by antibodies and complement or binding to blood coagulation factors can be completely prevented or significantly dampened. In fact, geneti-chemically modified Ad5-based viral particles exhibited strongly improved pharmacokinetics after intravenous delivery.13 On the basis of their patented findings and with funding from the German Federal Ministry of Education and Research (BMBF) GO-Bio program and BMWi’s EXIST Transfer of Research program, the Witten group is currently founding the spin-off company Ad-O-Lytics.* Ongoing work includes analysis of the viruses in various mouse tumor models and toxicity studies. The goal is to bring geneti-chemically modified OAds into the clinic.
Funding Information:
The authors acknowledge funding of their research by the German Federal Ministry of Education and Research (BMBF), the German Federal Ministry for Economic Affairs and Energy (BMWi), the German Research Council (DFG), the Helmholtz Association (HGF), German Cancer Aid (DKH), German Children Cancer Aid (DKS), the Wilhelm Sander Stiftung, the Monika Kutzner-Stiftung, the Else Kröner-Fresenius-Stiftung, the Stiftung für Krebs-und Scharlachforschung, the Wieland-Stiftung Heidelberg, the German–Israeli Foundation for Scientific Research and Development (GIF), and the Institut National de la Santé et de la Recherche Médicale (INSERM). J.R. and A.M. also acknowledge funding support from Oryx GmbH.
Funding Information:
For this study, the GMP-grade viral suspension will be provided by Vyriad Inc. in Rochester, Minnesota (a Mayo Clinic spin-off; CEO, Stephen J. Russell). Sponsor of this IIT is the NCT, Heidelberg. This trial is supported by MSD Sharp & Dohme GmbH (Haar, Germany).
Publisher Copyright:
© 2017, Mary Ann Liebert, Inc. 2017.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future.
AB - Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future.
UR - http://www.scopus.com/inward/record.url?scp=85030320551&partnerID=8YFLogxK
U2 - 10.1089/hum.2017.138
DO - 10.1089/hum.2017.138
M3 - Article
C2 - 28870120
AN - SCOPUS:85030320551
SN - 1043-0342
VL - 28
SP - 800
EP - 819
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 10
ER -