Antigen-specific oncolytic MV-based tumor vaccines through presentation of selected tumor-associated antigens on infected cells or virus-like particles

Hutzler, Stefan; Erbar, Stephanie; Jabulowsky, Robert A.; Hanauer, Jan R.H.; Schnotz, Jürgen H.; Beissert, Tim; Bodmer, Bianca S.; Eberle, Regina; Boller, Klaus; Klamp, Thorsten; Şahin, Uğur; Mühlebach, Michael D.

doi:10.1038/s41598-017-16928-8

Cited by 23 publications

(20 citation statements)

References 70 publications

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“…Thus, Maraba virus is currently applied in heterologous prime-boost settings with replication-deficient adenoviral vectors [64]. Previous work by Mühlebach and colleagues [31] and the present data support the notion that measles vaccines can be used for priming in oncolytic vaccination regimens.…”

Section: Discussionsupporting

confidence: 82%

“…As another approach to direct the immune response against the tumor, oncolytic viruses encoding tumor antigens have been developed [24][25][26][27][28][29][30][31]. Different antigen expression strategies have been realized in recombinant viral vectors for tumor vaccination.…”

Section: Introductionmentioning

confidence: 99%

“…For the treatment of HPV-associated cancers, Atherton et al generated vectors encoding full-length HPV 16 and 18 E6 and E7 separated by linker sequences to mediate proteasomal degradation [30]. Mühlebach and colleagues have designed recombinant measles vaccines encoding the full-length Claudin 6 tumor antigen either alone or in combination with murine leukemia virus (MLV) gag [31]. The latter strategy enables incorporation of the antigen into MLV virus-like particles (VLPs) to increase immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

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Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Busch

Kubon

Mayer

et al. 2020

Viruses

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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.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Busch

Kubon

Mayer

et al. 2020

Viruses

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“…Also, a number of antigens from other pathogens, including flaviviruses (27)(28)(29) and even Helicobacter pylori (33), have been among the targets, revealing the broad applicability of MV as a vaccine platform. Thus, MV-derived vaccines take advantage of the live-attenuated nature of the MV-derived backbone, which is a powerful immune stimulator triggering both humoral and cellular responses against homologous, as well as heterologous, antigens (34). Moreover, the natural tropism of vaccine strain MV for lymphatic cells, including professional antigen-presenting cells (35), most likely acts as a boost.…”

Section: Discussionmentioning

confidence: 99%

A Measles Virus-Based Vaccine Candidate Mediates Protection against Zika Virus in an Allogeneic Mouse Pregnancy Model

Nürnberger

Bodmer

Fiedler

et al. 2019

J Virol

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The impact of the Zika virus (ZIKV) epidemic highlights the need for vaccines that reduce or prevent infection and reliably prevent teratogenic complications. The live-attenuated measles virus (MV) vaccine strains are a promising vaccine platform, since they induce robust humoral and cellular immune responses against additional antigens and have an excellent safety record. To explore its potential to protect against ZIKV, we compared a recombinant Schwarz strain MV that encodes ZIKV prM and soluble E proteins (MV-Zika-sE) with a prototypic alum-adjuvanted whole inactivated ZIKV particle vaccine. Analysis of MV-Zika-sE-infected cells confirmed antigen expression, and the virus replicated with vaccine strain characteristics. Immunized IFNAR Ϫ/Ϫ -CD46Ge mice developed E protein-specific and neutralizing antibodies, and ZIKV E-specific cellular immune responses were observed by gamma interferon (IFN-␥) enzyme-linked immunospot (ELISpot) and in vitro T cell proliferation assays. To analyze protective efficacy, vaccinated female mice were challenged with ZIKV after allogeneic mating. In MV-Zika-sE-vaccinated mice, weight gain was similar to that in uninfected mice, while no plasma viremia was detectable in the majority of the animals. In contrast, infected control animals gained less weight and experienced about 100-fold higher viremia over at least 3 days. Moreover, vaccination with MV-Zika-sE reduced the ZIKV load in different organs and the placentas and prevented infection of the fetus. Consequently, no fetal growth retardation, anemia, or death due to ZIKV infection was seen in MV-Zika-sE-vaccinated dams. In contrast, the inactivated ZIKV vaccine had little to no effect in our studies. Therefore, the MV-derived ZIKV vaccine is a promising candidate for further preclinical and clinical development. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne flavivirus that causes a variety of neurological complications, including congenital birth defects. Despite the urgent need, no ZIKV vaccine has yet been licensed. Recombinant vaccine strain-derived measles viruses (MV) constitute a promising vector platform to induce immunity against foreign pathogens by expressing antigens from additional transcription units while at the same time possessing a remarkable safety profile. This concept has already been validated against different pathogens, including at least 3 other flaviviruses, and our data show that vaccination with MV expressing soluble ZIKV E protein significantly diminishes infection and prevents fetal loss or damage in an allogeneic mouse pregnancy model. It can thus be regarded as a promising emergency vaccine candidate with the potential for inclusion in routine vaccination settings in areas of endemicity to prevent teratogenic effects of circulating ZIKV during pregnancy, comparable to standard rubella virus vaccination.

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“…One pre-clinical study on recombinant measles virus VLPs expressing the tumor-specific antigen claudin-6 triggered claudin-6-specific immune responses in melanoma mouse models, ultimately inhibiting tumor metastasis. 109 While generally pre-existing immunity for oncolytic viruses reduces their efficacy, a contrary finding was reported in the case of Newcastle disease viruses (NDV) where an augmented therapeutic effect was observed in melanoma mouse models in the presence of NDV-specific antibodies through potentiation of systemic anti-tumor immunity. 110…”

Section: Virus Neutralizationmentioning

confidence: 99%

<p>Virus–Receptor Interactions and Virus Neutralization: Insights for Oncolytic Virus Development</p>

Jayawardena¹,

Poirier²,

Burga³

et al. 2020

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Oncolytic viruses (OVs) are replication competent agents that selectively target cancer cells. After penetrating the tumor cell, viruses replicate and eventually trigger cell lysis, releasing the new viral progeny, which at their turn will attack and kill neighbouring cells. The ability of OVs to self-amplify within the tumor while sparing normal cells can provide several advantages including the capacity to encode and locally produce therapeutic protein payloads, and to prime the host immune system. OVs targeting of cancer cells is mediated by host factors that are differentially expressed between normal tissue and tumors, including viral receptors and internalization factors. In this review article, we will discuss the evolution of oncolytic viruses that have reached the stage of clinical trials, their mechanisms of oncolysis, cellular receptors, strategies for targeting cancers, viral neutralization and developments to bypass virus neutralization.

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Antigen-specific oncolytic MV-based tumor vaccines through presentation of selected tumor-associated antigens on infected cells or virus-like particles

Cited by 23 publications

References 70 publications

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

A Measles Virus-Based Vaccine Candidate Mediates Protection against Zika Virus in an Allogeneic Mouse Pregnancy Model

<p>Virus–Receptor Interactions and Virus Neutralization: Insights for Oncolytic Virus Development</p>

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