Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

Berkeley, Robert A.; Steele, Lynette P.; Mulder, Aat A.; Wollenberg, Diana J.M. van den; Kottke, Timothy; Thompson, Jill; Coffey, Matthew; Hoeben, Rob C.; Vile, Richard G.; Melcher, Alan; Ilett, Elizabeth J.

doi:10.1158/2326-6066.cir-18-0309

Cited by 56 publications

(49 citation statements)

References 22 publications

(30 reference statements)

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“…However, pre-existing anti-measles immunity did not affect anti-CHIKV immune responses in human subjects [10]. In the context of oncolytic virotherapy, pre-existing anti-viral immunity may even be conducive to anti-tumor efficacy [21,71,72].…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Busch

Kubon

Mayer

et al. 2020

Viruses

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“…113 Furthermore, antibodyneutralized reovirus complex can be introduced into human monocytes, where internalized complexes were processed to release infectious particles, ultimately targeting cancer cells. 114 Mesenchymal stem cells (MSCs) have been used as a delivery system for chimeric human ade-novirus5/3 (HAdV5/3) with the primary purpose of masking the virus from immune attack. 115 The cellular receptor for HAdV5 entry, coxsackievirus and adenovirus receptor (CAR) is poorly expressed in MSCs.…”

Section: Cell Carriersmentioning

confidence: 99%

“…Another example for use of bifunctional adapters arises from a recent study on oncolytic adenovirus hTert-Ad treatment in combination with DE1scFv-pSia protein containing a DE1 domain of adenovirus hexon and a polysialic acid-specific single-chain variable fragment (scFv) to capture neutralizing antibodies and for tumor cell recognition, respectively. 125 • In vivo study against lung cancer 111 • In vivo study against metastatic melanoma 112,113 • In vivo study against melanoma 114 • In vitro study against pancreatic cancer 115 • In vivo study against ovarian cancer 131…”

Section: Other Strategiesmentioning

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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“…Intriguingly, it was also shown that when human monocytes were loaded with preformed reovirus-antibody complexes (neutralizing the reovirus) they were able to deliver fully replication competent reovirus to tumor cells in vitro. In vivo administration of neutralized reovirus-antibody complexes were also shown to slow B16 mouse melanoma tumor growth compared to vehicle only [163]. A range of cell types have been used as cell carriers for variety of OV and the preclinical success of these have been well reviewed by Roy et al [164] Determining which cell is best to use for different tumor indications is an important consideration when implementing carrier cell systems.…”

Section: Cell Carriersmentioning

confidence: 99%

Achieving systemic delivery of oncolytic viruses

Hill

Carlisle

2019

Expert Opinion on Drug Delivery

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Introduction: Oncolytic virotherapy is a selective and powerful tool for cancer treatment. Studies proving the ability of oncolytic viruses (OVs) to target and rapidly kill cancer cells have led to approval of H101 and Imlygic®. Both these OVs are restricted to intratumoral administration into cancer lesions. Despite promising preclinical results, systemic delivery of OV has shown limited success in patients due to a knockdown in infectivity, as a result of rapid immune-mediated neutralization, and poor penetration into tumors. Areas covered: This review catalogs the techniques used to enhance OV delivery. Firstly, insights from clinical trials of OV provide evidence of the need for enhanced delivery strategies. Secondly, the techniques applied to overcome the challenges highlighted by clinical trial data (i.e. suboptimal pharmacokinetics, antiviral immune responses, and poor penetration into solid tumors) are reviewed. Expert opinion: For OV to gain traction and convert potential into value, researchers focussed on showing clinical and commercial viability following intratumoral injection. For the technology to mature and become applicable across a wider range of patients/cancer indications, amenability to systemic delivery is required. This may be achieved using strategies that modulate the OV by genetic or chemical means and/or that alter the physiology of target tumors. ARTICLE HISTORY

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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

Cited by 56 publications

References 22 publications

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

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

Achieving systemic delivery of oncolytic viruses

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