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Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists.
Viruses 2019; 11(10)V

Abstract

Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation.

Authors+Show Affiliations

National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. paul.backhaus@web.de. Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. paul.backhaus@web.de. Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany. paul.backhaus@web.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. ruta.veinalde@biomed.lu.lv. Present address: Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia. ruta.veinalde@biomed.lu.lv.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. laura.hartmann@dkfz-heidelberg.de. German Cancer Research Center, 69120 Heidelberg, Germany. laura.hartmann@dkfz-heidelberg.de. Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany. laura.hartmann@dkfz-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. jessica.dunder@nct-heidelberg.de. Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. jessica.dunder@nct-heidelberg.de. Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany. jessica.dunder@nct-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. lara.jeworowski@ewetel.net.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. jessica.albert@nct-heidelberg.de. Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. jessica.albert@nct-heidelberg.de. Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. jessica.albert@nct-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. birgit.hoyler@nct-heidelberg.de. Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. birgit.hoyler@nct-heidelberg.de. Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. birgit.hoyler@nct-heidelberg.de.CMCP-Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany. tanja.poth@med.uni-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. dirk.jaeger@nct-heidelberg.de. German Cancer Research Center, 69120 Heidelberg, Germany. dirk.jaeger@nct-heidelberg.de. Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. dirk.jaeger@nct-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. guy.ungerechts@nct-heidelberg.de. Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. guy.ungerechts@nct-heidelberg.de. Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. guy.ungerechts@nct-heidelberg.de. Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada. guy.ungerechts@nct-heidelberg.de.National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. christine.engeland@nct-heidelberg.de. Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. christine.engeland@nct-heidelberg.de. Research Group Mechanisms of Oncolytic Immunotherapy, Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany. christine.engeland@nct-heidelberg.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31623390

Citation

Backhaus, Paul S., et al. "Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists." Viruses, vol. 11, no. 10, 2019.
Backhaus PS, Veinalde R, Hartmann L, et al. Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists. Viruses. 2019;11(10).
Backhaus, P. S., Veinalde, R., Hartmann, L., Dunder, J. E., Jeworowski, L. M., Albert, J., ... Engeland, C. E. (2019). Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists. Viruses, 11(10), doi:10.3390/v11100914.
Backhaus PS, et al. Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists. Viruses. 2019 Oct 3;11(10) PubMed PMID: 31623390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists. AU - Backhaus,Paul S, AU - Veinalde,Rūta, AU - Hartmann,Laura, AU - Dunder,Jessica E, AU - Jeworowski,Lara M, AU - Albert,Jessica, AU - Hoyler,Birgit, AU - Poth,Tanja, AU - Jäger,Dirk, AU - Ungerechts,Guy, AU - Engeland,Christine E, Y1 - 2019/10/03/ PY - 2019/08/04/received PY - 2019/09/20/revised PY - 2019/09/29/accepted PY - 2019/10/19/entrez KW - cancer immunotherapy KW - interleukin-12 KW - interleukin-15 KW - measles virus KW - oncolytic virus JF - Viruses JO - Viruses VL - 11 IS - 10 N2 - Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/31623390/Immunological_Effects_and_Viral_Gene_Expression_Determine_the_Efficacy_of_Oncolytic_Measles_Vaccines_Encoding_IL-12_or_IL-15_Agonists L2 - http://www.mdpi.com/resolver?pii=v11100914 DB - PRIME DP - Unbound Medicine ER -