Editorial

2 pages, 152 KiB

Open AccessEditorial

Special Issue “Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy”

by Liang-Tzung Lin

Viruses 2020, 12(3), 341; https://doi.org/10.3390/v12030341 - 20 Mar 2020

Viewed by 1942

Members of the Morbillivirus genus are enveloped, negative-strand RNA viruses that include a number of highly contagious pathogens important to humans and animals [...] Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

Research

Jump to: Editorial, Review

17 pages, 2193 KiB

Open AccessArticle

Measles Vaccines Designed for Enhanced CD8⁺ T Cell Activation

by Elena Busch, Kristina D. Kubon, Johanna K. M. Mayer, Gemma Pidelaserra-Martí, Jessica Albert, Birgit Hoyler, Johannes P. W. Heidbuechel, Kyle B. Stephenson, Brian D. Lichty, Wolfram Osen, Stefan B. Eichmüller, Dirk Jäger, Guy Ungerechts and Christine E. Engeland

Viruses 2020, 12(2), 242; https://doi.org/10.3390/v12020242 - 21 Feb 2020

Cited by 14 | Viewed by 4874

Abstract

Priming and activation of CD8⁺ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics [...] Read more.

Priming and activation of CD8⁺ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8⁺ T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8⁺ epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8⁺ T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8⁺ responses against pathogens and tumor antigens. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

21 pages, 3612 KiB

Open AccessArticle

Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro

by Federico Armando, Matteo Gambini, Attilio Corradi, Chiara Giudice, Vanessa Maria Pfankuche, Graham Brogden, Friederike Attig, Maren von Köckritz-Blickwede, Wolfgang Baumgärtner and Christina Puff

Viruses 2020, 12(2), 200; https://doi.org/10.3390/v12020200 - 11 Feb 2020

Cited by 14 | Viewed by 3720

Abstract

Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. [...] Read more.

Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1α and its angiogenic downstream pathway in DH82 cells in vitro. Microarray data analysis, immunofluorescence for 8-hydroxyguanosine, superoxide dismutase 2 and catalase, and flow cytometry for oxidative burst displayed an increased oxidative stress in persistently CDV-infected DH82 cells (DH82Ond pi) compared to controls. The HIF-1α expression in DH82Ond pi increased, as demonstrated by Western blot, and showed an unexpected, often sub-membranous distribution, as shown by immunofluorescence and immunoelectron microscopy. Furthermore, microarray data analysis and immunofluorescence confirmed a reduced expression of VEGF-B in DH82Ond pi compared to controls. In summary, these results suggest a reduced activation of the HIF-1α angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1α triggered by a CDV-induced increased oxidative stress. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

23 pages, 6799 KiB

Open AccessArticle

The Susceptibility of Human Melanoma Cells to Infection with the Leningrad-16 Vaccine Strain of Measles Virus

by Yulia Ammour, Oxana Ryabaya, Yulia Shchetinina, Elena Prokofeva, Marina Gavrilova, Dmitry Khochenkov, Denis Vorobyev, Evgeny Faizuloev, Igor Shohin, Vitaly V. Zverev, Oxana Svitich and Tatiana Nasedkina

Viruses 2020, 12(2), 173; https://doi.org/10.3390/v12020173 - 04 Feb 2020

Cited by 13 | Viewed by 2993

Abstract

Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human [...] Read more.

Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

21 pages, 2834 KiB

Open AccessArticle

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

by Paul S. Backhaus, Rūta Veinalde, Laura Hartmann, Jessica E. Dunder, Lara M. Jeworowski, Jessica Albert, Birgit Hoyler, Tanja Poth, Dirk Jäger, Guy Ungerechts and Christine E. Engeland

Viruses 2019, 11(10), 914; https://doi.org/10.3390/v11100914 - 03 Oct 2019

Cited by 35 | Viewed by 4309

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

16 pages, 1545 KiB

Open AccessArticle

Forced Degradation Studies to Identify Critical Process Parameters for the Purification of Infectious Measles Virus

by Daniel Loewe, Julian Häussler, Tanja A. Grein, Hauke Dieken, Tobias Weidner, Denise Salzig and Peter Czermak

Viruses 2019, 11(8), 725; https://doi.org/10.3390/v11080725 - 07 Aug 2019

Cited by 21 | Viewed by 5731

Abstract

Oncolytic measles virus (MV) is a promising treatment for cancer but titers of up to 10¹¹ infectious particles per dose are needed for therapeutic efficacy, which requires an efficient, robust, and scalable production process. MV is highly sensitive to process conditions, and [...] Read more.

Oncolytic measles virus (MV) is a promising treatment for cancer but titers of up to 10¹¹ infectious particles per dose are needed for therapeutic efficacy, which requires an efficient, robust, and scalable production process. MV is highly sensitive to process conditions, and a substantial fraction of the virus is lost during current purification processes. We therefore conducted forced degradation studies under thermal, pH, chemical, and mechanical stress to determine critical process parameters. We found that MV remained stable following up to five freeze–thaw cycles, but was inactivated during short-term incubation (< 2 h) at temperatures exceeding 35 °C. The infectivity of MV declined at pH < 7, but was not influenced by different buffer systems or the ionic strength/osmolality, except high concentrations of CaCl₂ and MgSO₄. We observed low shear sensitivity (dependent on the flow rate) caused by the use of a peristaltic pump. For tangential flow filtration, the highest recovery of MV was at a shear rate of ~5700 s⁻¹. Our results confirm that the application of forced degradation studies is important to identify critical process parameters for MV purification. This will be helpful during the early stages of process development, ensuring the recovery of high titers of active MV particles after purification. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Graphical abstract

22 pages, 3520 KiB

Open AccessArticle

Starvation-Induced Differential Virotherapy Using an Oncolytic Measles Vaccine Virus

by Gabriel Scheubeck, Susanne Berchtold, Irina Smirnow, Andrea Schenk, Julia Beil and Ulrich M. Lauer

Viruses 2019, 11(7), 614; https://doi.org/10.3390/v11070614 - 05 Jul 2019

Cited by 9 | Viewed by 3342

Abstract

Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting [...] Read more.

Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting normal cells against off-target lysis. Human colorectal carcinoma (CRC) cell lines as well as human normal colon cell lines were subjected to various starvation regimes and infected with MeV-GFP. The applied fasting regimes were either short-term (24 h pre-infection) or long-term (24 h pre- plus 96 h post-infection). Cell-killing features of (i) virotherapy, (ii) starvation, as well as (iii) the combination of both were analyzed by cell viability assays and virus growth curves. Remarkably, while long-term low-serum, standard glucose starvation potentiated the efficacy of MeV-mediated cell killing in CRC cells, it was found to be decreased in normal colon cells. Interestingly, viral replication of MeV-GFP in CRC cells was decreased in long-term-starved cells and increased after short-term low-glucose, low-serum starvation. In conclusion, starvation-based virotherapy has the potential to differentially enhance MeV-mediated oncolysis in the context of CRC cancer patients while protecting normal colon cells from unwanted off-target effects. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

20 pages, 5190 KiB

Open AccessReview

Viral Pathogenesis, Recombinant Vaccines, and Oncolytic Virotherapy: Applications of the Canine Distemper Virus Reverse Genetics System

by Jianjun Zhao, Yanrong Ren, Jie Chen, Jiasan Zheng and Dongbo Sun

Viruses 2020, 12(3), 339; https://doi.org/10.3390/v12030339 - 20 Mar 2020

Cited by 9 | Viewed by 6795

Abstract

Canine distemper virus (CDV) is a highly contagious pathogen transmissible to a broad range of terrestrial and aquatic carnivores. Despite the availability of attenuated vaccines against CDV, the virus remains responsible for outbreaks of canine distemper (CD) with significant morbidity and mortality in [...] Read more.

Canine distemper virus (CDV) is a highly contagious pathogen transmissible to a broad range of terrestrial and aquatic carnivores. Despite the availability of attenuated vaccines against CDV, the virus remains responsible for outbreaks of canine distemper (CD) with significant morbidity and mortality in domesticated and wild carnivores worldwide. CDV uses the signaling lymphocytic activation molecule (SLAM, or CD150) and nectin-4 (PVRL4) as entry receptors, well-known tumor-associated markers for several lymphadenomas and adenocarcinomas, which are also responsible for the lysis of tumor cells and apparent tumor regression. Thus, CDV vaccine strains have emerged as a promising platform of oncolytic viruses for use in animal cancer therapy. Recent advances have revealed that use of the CDV reverse genetic system (RGS) has helped increase the understanding of viral pathogenesis and explore the development of recombinant CDV vaccines. In addition, genetic engineering of CDV based on RGS approaches also has the potential of enhancing oncolytic activity and selectively targeting tumors. Here, we reviewed the host tropism and pathogenesis of CDV, and current development of recombinant CDV-based vaccines as well as their use as oncolytic viruses against cancers. Full article

(This article belongs to the Special Issue Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI