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Open AccessArticle

Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists

1
National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
2
Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany
3
Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
4
Present address: Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia
5
German Cancer Research Center, 69120 Heidelberg, Germany
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Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany
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Department of Medical Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany
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CMCP—Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
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Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
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Research Group Mechanisms of Oncolytic Immunotherapy, Clinical Cooperation Unit Virotherapy, German Cancer Research Center, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2019, 11(10), 914; https://doi.org/10.3390/v11100914
Received: 4 August 2019 / Revised: 20 September 2019 / Accepted: 29 September 2019 / Published: 3 October 2019
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. View Full-Text
Keywords: cancer immunotherapy; oncolytic virus; measles virus; interleukin-12; interleukin-15 cancer immunotherapy; oncolytic virus; measles virus; interleukin-12; interleukin-15
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Backhaus, P.S.; Veinalde, R.; Hartmann, L.; Dunder, J.E.; Jeworowski, L.M.; Albert, J.; Hoyler, B.; Poth, T.; Jäger, D.; Ungerechts, G.; Engeland, C.E. Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists. Viruses 2019, 11, 914.

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