Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies

Dirk M. Nettelbeck; Mathias F. Leber; Jennifer Altomonte; Assia Angelova; Julia Beil; Susanne Berchtold; Maike Delic; Jürgen Eberle; Anja Ehrhardt; Christine E. Engeland; Henry Fechner; Karsten Geletneky; Katrin Goepfert; Per Sonne Holm; Stefan Kochanek; Florian Kreppel; Lea Krutzke; Florian Kühnel; Karl Sebastian Lang; Antonio Marchini; Markus Moehler; Michael D. Mühlebach; Ulrike Naumann; Roman Nawroth; Jürg Nüesch; Jean Rommelaere; Ulrich M. Lauer; Guy Ungerechts

doi:10.3390/v13081420

Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies

Dirk M. Nettelbeck^*, Mathias F. Leber, Jennifer Altomonte, Assia Angelova, Julia Beil, Susanne Berchtold, Maike Delic, Jürgen Eberle, Anja Ehrhardt, Christine E. Engeland, Henry Fechner, Karsten Geletneky, Katrin Goepfert, Per Sonne Holm, Stefan Kochanek, Florian Kreppel, Lea Krutzke, Florian Kühnel, Karl Sebastian Lang, Antonio MarchiniMarkus Moehler, Michael D. Mühlebach, Ulrike Naumann, Roman Nawroth, Jürg Nüesch, Jean Rommelaere, Ulrich M. Lauer, Guy Ungerechts^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

26 Citations (Scopus)

Abstract

Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”— the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

Original language	English
Article number	1420
Journal	Viruses
Volume	13
Issue number	8
DOIs	https://doi.org/10.3390/v13081420
Publication status	Published - 21 Jul 2021

Keywords

Clinical trials
Combination therapy
Immunotherapy
Oncolytic virus
Research in Germany
Therapeutic transgene
Virotherapy
Virus engineering
Virus targeting

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10.3390/v13081420Licence: CC BY

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Nettelbeck, D. M., Leber, M. F., Altomonte, J., Angelova, A., Beil, J., Berchtold, S., Delic, M., Eberle, J., Ehrhardt, A., Engeland, C. E., Fechner, H., Geletneky, K., Goepfert, K., Holm, P. S., Kochanek, S., Kreppel, F., Krutzke, L., Kühnel, F., Lang, K. S., ... Ungerechts, G. (2021). Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies. Viruses, 13(8), Article 1420. https://doi.org/10.3390/v13081420

@article{95c1d55ff5d445488ef33051a646e9f3,

title = "Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies",

abstract = "Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”— the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.",

keywords = "Clinical trials, Combination therapy, Immunotherapy, Oncolytic virus, Research in Germany, Therapeutic transgene, Virotherapy, Virus engineering, Virus targeting",

author = "Nettelbeck, {Dirk M.} and Leber, {Mathias F.} and Jennifer Altomonte and Assia Angelova and Julia Beil and Susanne Berchtold and Maike Delic and J{\"u}rgen Eberle and Anja Ehrhardt and Engeland, {Christine E.} and Henry Fechner and Karsten Geletneky and Katrin Goepfert and Holm, {Per Sonne} and Stefan Kochanek and Florian Kreppel and Lea Krutzke and Florian K{\"u}hnel and Lang, {Karl Sebastian} and Antonio Marchini and Markus Moehler and M{\"u}hlebach, {Michael D.} and Ulrike Naumann and Roman Nawroth and J{\"u}rg N{\"u}esch and Jean Rommelaere and Lauer, {Ulrich M.} and Guy Ungerechts",

note = "Funding Information: The groups of Per Sonne Holm and Roman Nawroth at the Technical University of Munich (PSH is now at Medical University Innsbruck), in collaboration with the group of Ulrike Naumann at the Hertie Institute for Clinical Brain Research in T{\"u}bingen and the group of Uwe Thiel and Sebastian Schober at Children{\textquoteright}s Hospital Schwabing are focusing on further developing their previously established YB-1-dependent oAd XVir-N-31 (see [28]) for treatment of glioblastoma, bladder cancer, and sarcoma. Explored treatment modalities include the combination with targeted therapy approaches, radiation or immune checkpoint inhibition. In this regard, the investigators have recently demonstrated that tumor irradiation, temozolomide or STAT 3/5 inhibitors further strengthened the therapeutic impact of XVir-N-31 in glioma-bearing mice, as well as in bladder cancer [43–45], indicating the benefit of combining oAds with established therapies. Currently, the therapeutic effects of XVir-N-31 are evaluated in combination with cyclin-dependent kinase (CDK) 4/6 and bromodomain inhibitors (BETi), both known to affect the cell cycle upon targeting the RB/E2F pathway. Results from the past years indicate strong synergistic effects, and ongoing research is focusing on the molecular basis for the observed strong increase in cell killing. Importantly, the increase in cell killing is accompanied with a further stimulation of the immune response. Furthermore, immune-stimulatory effects of a derivate of XVir-N-31 that expresses a humanized antibody against PD-L1 are being evaluated in experimental glioma using immuno-humanized mice. Initial results support previous findings from other groups, indicating that the immune response against tumor antigens plays a central role in the therapeutic effect of oAd. Based on the results from the past years, and together with the spin-off company XVir Therapeutics GmbH and supported by the German Ministry of Education and Research (BMBF) and German Cancer Aid, clinical phase I/II trials with XVir-N-31 are in preparation for the treatment of glioblastoma and sarcoma. Funding Information: Conflicts of Interest: J.A. is co-inventor on a patent of the VSV-NDV technology. C.E.E. is listed as coinventor on patent (applications) related to oncolytic measles viruses as (cancer) immunotherapeutics. H.F. has patented the CVB3 variant PD for use in cancer therapy and have a patent pending for treatment of cancer using miR-TS in oncolytic CVB3. P.S.H. is cofounder of XVir Therapeutics GmbH. K.S.L. is involved in the development of LCMV for clinical application in oncology in cooperation with and as co-founder of Abalos Therapeutics GmbH. The clinical studies of ParvOryx were sponsored by Oryx GmbH & Co. K.G., J.R., A.A., and A.M. received research grants from Oryx GmbH. J.R., A.M., A.A., and K.G. are co-inventors of various patents (applications) relating to the content of this review. M.M. received research grants from Amgen and Transgene SA, Illkirch-Graffenstaden, Alsace, France (JX-GFP and TG6002 research). The MASTERKEY-265/KEYNOTE-034 trial (NCT02263508) was sponsored by Amgen Inc., Thousand Oaks, CA, USA. G.U. is founder, and CMO/CSO of CanVirex AG, a company developing oncolytic measles viruses as (cancer) immunotherapeutics. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Funding Information: Research activities in the authors? labs were funded by the Wilhelm Sander-Stiftung, grant 2020.069.1 (D.M.N.); by the German Research Association (DFG) Sonderforschungsbereich (SFB) 824 subproject C7, the German Cancer Aid, grant 70113272, and the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation program, grant agreement No. 853433 (J.A.); by the German Research Association (DFG), grant EH 192/5-1 (A.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70112382 (J.E.); by the German Research Association (DFG), grant EN 1119/2-2, the Wilhelm Sander-Stiftung, grant 2018.058.1 and the Else Kr?ner-Fresenius-Stiftung (2019_EKMS.02) (C.E.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant 70112382, the Wilhelm Sander-Stiftung, grant 2017.101.1, the Technische Universit?t Berlin internal research tool ProTUTec, grant 17011/TUB and the excellence strategy of the Federation and Federal States by the Berlin University Alliance (H.F.); by the German Federal Ministry of Education and Research (BMBF) and the Federal States of Germany grant ?Innovative Hochschule? FKZ 3IHS024D (S.K.); by the Center for Biomedical Education and Research (ZBAF) at University Witten/Herdecke (F.Kr.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70113873 (F.K?.); by the Luxembourg Cancer Foundation, T?l?vie and the Cooperational Research Program of the German Cancer Research Center (DKFZ), Heidelberg with the Ministry of Science and Technology, Israel and a generous donation from Andr? Welter (A.M.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 109614, the CI3 Cutting Edge Cluster Funding of the Federal German Ministry of Education and Research of Germany (BMBF) grant 031A010B (M.D.M.); by Oryx GmbH & Co. KG, Oncolytic Virus R&D program (J.R., A.M., A.A., and K.G.); by the German Cancer Consortium (DKTK) of the German Cancer Research Center (DKFZ) (U.M.L.); by the Alois Hirdt-Erben-und Wieland Stiftung grant 230/13/BA/00 (G.U.). Funding Information: Funding: Research activities in the authors{\textquoteright} labs were funded by the Wilhelm Sander-Stiftung, grant 2020.069.1 (D.M.N.); by the German Research Association (DFG) Sonderforschungsbereich (SFB) 824 subproject C7, the German Cancer Aid, grant 70113272, and the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program, grant agreement No. 853433 (J.A.); by the German Research Association (DFG), grant EH 192/5-1 (A.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70112382 (J.E.); by the German Research Association (DFG), grant EN 1119/2-2, the Wilhelm Sander-Stiftung, grant 2018.058.1 and the Else Kr{\"o}ner-Fresenius-Stiftung (2019_EKMS.02) (C.E.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant 70112382, the Wilhelm Sander-Stiftung, grant 2017.101.1, the Technische Universit{\"a}t Berlin internal research tool ProTUTec, grant 17011/TUB and the excellence strategy of the Federation and Federal States by the Berlin University Alliance (H.F.); by the German Federal Ministry of Education and Research (BMBF) and the Federal States of Germany grant “Innovative Hochschule” FKZ 3IHS024D (S.K.); by the Center for Biomedical Education and Research (ZBAF) at University Witten/Herdecke (F.Kr.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70113873 (F.K{\"u}.); by the Luxembourg Cancer Foundation, T{\'e}l{\'e}vie and the Cooperational Research Program of the German Cancer Research Center (DKFZ), Heidelberg with the Ministry of Science and Technology, Israel and a generous donation from Andr{\'e} Welter (A.M.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 109614, the CI3 Cutting Edge Cluster Funding of the Federal German Ministry of Education and Research of Germany (BMBF) grant 031A010B (M.D.M.); by Oryx GmbH & Co. KG, Oncolytic Virus R&D program (J.R., A.M., A.A., and K.G.); by the German Cancer Consortium (DKTK) of the German Cancer Research Center (DKFZ) (U.M.L.); by the Alois Hirdt-Erben-und Wieland Stiftung grant 230/13/BA/00 (G.U.) Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = jul,

day = "21",

doi = "10.3390/v13081420",

language = "English",

volume = "13",

journal = "Viruses",

issn = "1999-4915",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "8",

}

Nettelbeck, DM, Leber, MF, Altomonte, J, Angelova, A, Beil, J, Berchtold, S, Delic, M, Eberle, J, Ehrhardt, A, Engeland, CE, Fechner, H, Geletneky, K, Goepfert, K, Holm, PS, Kochanek, S, Kreppel, F, Krutzke, L, Kühnel, F, Lang, KS, Marchini, A, Moehler, M, Mühlebach, MD, Naumann, U, Nawroth, R, Nüesch, J, Rommelaere, J, Lauer, UM & Ungerechts, G 2021, 'Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies', Viruses, vol. 13, no. 8, 1420. https://doi.org/10.3390/v13081420

TY - JOUR

T1 - Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies

AU - Nettelbeck, Dirk M.

AU - Leber, Mathias F.

AU - Altomonte, Jennifer

AU - Angelova, Assia

AU - Beil, Julia

AU - Berchtold, Susanne

AU - Delic, Maike

AU - Eberle, Jürgen

AU - Ehrhardt, Anja

AU - Engeland, Christine E.

AU - Fechner, Henry

AU - Geletneky, Karsten

AU - Goepfert, Katrin

AU - Holm, Per Sonne

AU - Kochanek, Stefan

AU - Kreppel, Florian

AU - Krutzke, Lea

AU - Kühnel, Florian

AU - Lang, Karl Sebastian

AU - Marchini, Antonio

AU - Moehler, Markus

AU - Mühlebach, Michael D.

AU - Naumann, Ulrike

AU - Nawroth, Roman

AU - Nüesch, Jürg

AU - Rommelaere, Jean

AU - Lauer, Ulrich M.

AU - Ungerechts, Guy

N1 - Funding Information: The groups of Per Sonne Holm and Roman Nawroth at the Technical University of Munich (PSH is now at Medical University Innsbruck), in collaboration with the group of Ulrike Naumann at the Hertie Institute for Clinical Brain Research in Tübingen and the group of Uwe Thiel and Sebastian Schober at Children’s Hospital Schwabing are focusing on further developing their previously established YB-1-dependent oAd XVir-N-31 (see [28]) for treatment of glioblastoma, bladder cancer, and sarcoma. Explored treatment modalities include the combination with targeted therapy approaches, radiation or immune checkpoint inhibition. In this regard, the investigators have recently demonstrated that tumor irradiation, temozolomide or STAT 3/5 inhibitors further strengthened the therapeutic impact of XVir-N-31 in glioma-bearing mice, as well as in bladder cancer [43–45], indicating the benefit of combining oAds with established therapies. Currently, the therapeutic effects of XVir-N-31 are evaluated in combination with cyclin-dependent kinase (CDK) 4/6 and bromodomain inhibitors (BETi), both known to affect the cell cycle upon targeting the RB/E2F pathway. Results from the past years indicate strong synergistic effects, and ongoing research is focusing on the molecular basis for the observed strong increase in cell killing. Importantly, the increase in cell killing is accompanied with a further stimulation of the immune response. Furthermore, immune-stimulatory effects of a derivate of XVir-N-31 that expresses a humanized antibody against PD-L1 are being evaluated in experimental glioma using immuno-humanized mice. Initial results support previous findings from other groups, indicating that the immune response against tumor antigens plays a central role in the therapeutic effect of oAd. Based on the results from the past years, and together with the spin-off company XVir Therapeutics GmbH and supported by the German Ministry of Education and Research (BMBF) and German Cancer Aid, clinical phase I/II trials with XVir-N-31 are in preparation for the treatment of glioblastoma and sarcoma. Funding Information: Conflicts of Interest: J.A. is co-inventor on a patent of the VSV-NDV technology. C.E.E. is listed as coinventor on patent (applications) related to oncolytic measles viruses as (cancer) immunotherapeutics. H.F. has patented the CVB3 variant PD for use in cancer therapy and have a patent pending for treatment of cancer using miR-TS in oncolytic CVB3. P.S.H. is cofounder of XVir Therapeutics GmbH. K.S.L. is involved in the development of LCMV for clinical application in oncology in cooperation with and as co-founder of Abalos Therapeutics GmbH. The clinical studies of ParvOryx were sponsored by Oryx GmbH & Co. K.G., J.R., A.A., and A.M. received research grants from Oryx GmbH. J.R., A.M., A.A., and K.G. are co-inventors of various patents (applications) relating to the content of this review. M.M. received research grants from Amgen and Transgene SA, Illkirch-Graffenstaden, Alsace, France (JX-GFP and TG6002 research). The MASTERKEY-265/KEYNOTE-034 trial (NCT02263508) was sponsored by Amgen Inc., Thousand Oaks, CA, USA. G.U. is founder, and CMO/CSO of CanVirex AG, a company developing oncolytic measles viruses as (cancer) immunotherapeutics. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Funding Information: Research activities in the authors? labs were funded by the Wilhelm Sander-Stiftung, grant 2020.069.1 (D.M.N.); by the German Research Association (DFG) Sonderforschungsbereich (SFB) 824 subproject C7, the German Cancer Aid, grant 70113272, and the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation program, grant agreement No. 853433 (J.A.); by the German Research Association (DFG), grant EH 192/5-1 (A.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70112382 (J.E.); by the German Research Association (DFG), grant EN 1119/2-2, the Wilhelm Sander-Stiftung, grant 2018.058.1 and the Else Kr?ner-Fresenius-Stiftung (2019_EKMS.02) (C.E.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant 70112382, the Wilhelm Sander-Stiftung, grant 2017.101.1, the Technische Universit?t Berlin internal research tool ProTUTec, grant 17011/TUB and the excellence strategy of the Federation and Federal States by the Berlin University Alliance (H.F.); by the German Federal Ministry of Education and Research (BMBF) and the Federal States of Germany grant ?Innovative Hochschule? FKZ 3IHS024D (S.K.); by the Center for Biomedical Education and Research (ZBAF) at University Witten/Herdecke (F.Kr.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70113873 (F.K?.); by the Luxembourg Cancer Foundation, T?l?vie and the Cooperational Research Program of the German Cancer Research Center (DKFZ), Heidelberg with the Ministry of Science and Technology, Israel and a generous donation from Andr? Welter (A.M.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 109614, the CI3 Cutting Edge Cluster Funding of the Federal German Ministry of Education and Research of Germany (BMBF) grant 031A010B (M.D.M.); by Oryx GmbH & Co. KG, Oncolytic Virus R&D program (J.R., A.M., A.A., and K.G.); by the German Cancer Consortium (DKTK) of the German Cancer Research Center (DKFZ) (U.M.L.); by the Alois Hirdt-Erben-und Wieland Stiftung grant 230/13/BA/00 (G.U.). Funding Information: Funding: Research activities in the authors’ labs were funded by the Wilhelm Sander-Stiftung, grant 2020.069.1 (D.M.N.); by the German Research Association (DFG) Sonderforschungsbereich (SFB) 824 subproject C7, the German Cancer Aid, grant 70113272, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program, grant agreement No. 853433 (J.A.); by the German Research Association (DFG), grant EH 192/5-1 (A.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70112382 (J.E.); by the German Research Association (DFG), grant EN 1119/2-2, the Wilhelm Sander-Stiftung, grant 2018.058.1 and the Else Kröner-Fresenius-Stiftung (2019_EKMS.02) (C.E.E.); by the German Cancer Aid (Deutsche Krebshilfe), grant 70112382, the Wilhelm Sander-Stiftung, grant 2017.101.1, the Technische Universität Berlin internal research tool ProTUTec, grant 17011/TUB and the excellence strategy of the Federation and Federal States by the Berlin University Alliance (H.F.); by the German Federal Ministry of Education and Research (BMBF) and the Federal States of Germany grant “Innovative Hochschule” FKZ 3IHS024D (S.K.); by the Center for Biomedical Education and Research (ZBAF) at University Witten/Herdecke (F.Kr.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 70113873 (F.Kü.); by the Luxembourg Cancer Foundation, Télévie and the Cooperational Research Program of the German Cancer Research Center (DKFZ), Heidelberg with the Ministry of Science and Technology, Israel and a generous donation from André Welter (A.M.); by the German Cancer Aid (Deutsche Krebshilfe), grant number: 109614, the CI3 Cutting Edge Cluster Funding of the Federal German Ministry of Education and Research of Germany (BMBF) grant 031A010B (M.D.M.); by Oryx GmbH & Co. KG, Oncolytic Virus R&D program (J.R., A.M., A.A., and K.G.); by the German Cancer Consortium (DKTK) of the German Cancer Research Center (DKFZ) (U.M.L.); by the Alois Hirdt-Erben-und Wieland Stiftung grant 230/13/BA/00 (G.U.) Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/7/21

Y1 - 2021/7/21

N2 - Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”— the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

AB - Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”— the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

KW - Clinical trials

KW - Combination therapy

KW - Immunotherapy

KW - Oncolytic virus

KW - Research in Germany

KW - Therapeutic transgene

KW - Virotherapy

KW - Virus engineering

KW - Virus targeting

UR - http://www.scopus.com/inward/record.url?scp=85111430945&partnerID=8YFLogxK

UR - https://www.ncbi.nlm.nih.gov/pubmed/34452286

U2 - 10.3390/v13081420

DO - 10.3390/v13081420

M3 - Review article

C2 - 34452286

AN - SCOPUS:85111430945

SN - 1999-4915

VL - 13

JO - Viruses

JF - Viruses

IS - 8

M1 - 1420

ER -

Virotherapy in germany—recent activities in virus engineering, preclinical development, and clinical studies

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