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Viruses
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Oncolytic Viruses Therapy
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Oncolytic Viruses Therapy

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 28361

Special Issue Editors

Dr. Elizabeth Ilett

E-Mail Website
Guest Editor
Leeds Institute of Medical Research, St James’ University Hospital, Leeds, UK
Interests: oncolytic viruses; cancer immunotherapy; innate and adaptive anti-tumour immune responses; solid tumours
Dr. Fiona Errington-Mais

E-Mail Website
Guest Editor
Leeds Institute of Medical Research, St James’ University Hospital, Leeds, UK
Interests: oncolytic viruses; cancer immunotherapy; innate and adaptive anti-tumour immune responses; haematological malignancies

Special Issue Information

Dear Colleagues,

Oncolytic viruses (OVs) are naturally occurring or genetically modified viruses that target tumour cells, while largely sparing normal cells. They were initially developed as cytotoxic agents, but are now known to mediate their anti-tumour effects largely via the activation of the host immune system.  No single OV has emerged as dominant in terms of efficacy, and it is unlikely that such an OV exists.  Furthermore, as single agents, oncolytic viruses have largely shown only moderate clinical benefit, and many challenges for realizing their full potential remain, including the following: the route of delivery; the impact of OV-specific immune responses on therapeutic efficacy, how to generate specific immune responses that target both the tumour and the supporting stroma, and the identification of combination therapies that maximize therapeutic outcome. Nonetheless, OVs remain a promising weapon in the immunotherapeutic armamentarium, and further viral modifications, together with informed scheduling and strategic combination with other treatments, will surely pay dividends for cancer patients.

In this Special Issue of Viruses, we aim to discuss the current understanding of the challenges faced by OV therapy and the latest developments in overcoming these hurdles to increase therapeutic efficacy.

Dr. Elizabeth Ilett
Dr. Fiona Errington-Mais
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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12 pages, 1778 KiB  
Article
Efficient Intravenous Tumor Targeting Using the αvβ6 Integrin-Selective Precision Virotherapy Ad5NULL-A20
by James A. Davies, Gareth Marlow, Hanni K. Uusi-Kerttula, Gillian Seaton, Luke Piggott, Luned M. Badder, Richard W. E. Clarkson, John D. Chester and Alan L. Parker
Viruses 2021, 13(5), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050864 - 08 May 2021
Cited by 7 | Viewed by 2934
Abstract
We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a [...] Read more.
We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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Review

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17 pages, 872 KiB  
Review
The Multifaceted Role of Macrophages in Oncolytic Virotherapy
by Laura Hofman, Sean E. Lawler and Martine L. M. Lamfers
Viruses 2021, 13(8), 1570; https://doi.org/10.3390/v13081570 - 09 Aug 2021
Cited by 12 | Viewed by 4090
Abstract
One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal [...] Read more.
One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host’s immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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12 pages, 919 KiB  
Review
Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells
by Elaine Y. L. Leung and Iain A. McNeish
Viruses 2021, 13(8), 1450; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081450 - 26 Jul 2021
Cited by 6 | Viewed by 2674
Abstract
Oncolytic viruses (OVs) are an emerging class of anti-cancer agents that replicate selectively within malignant cells and generate potent immune responses. Their potential efficacy has been shown in clinical trials, with talimogene laherparepvec (T-VEC or IMLYGIC®) now approved both in the United [...] Read more.
Oncolytic viruses (OVs) are an emerging class of anti-cancer agents that replicate selectively within malignant cells and generate potent immune responses. Their potential efficacy has been shown in clinical trials, with talimogene laherparepvec (T-VEC or IMLYGIC®) now approved both in the United States and Europe. In healthy individuals, NK cells provide effective surveillance against cancer and viral infections. In oncolytic viral therapy, NK cells may render OV ineffective by rapid elimination of the propagating virus but could also improve therapeutic efficacy by preferential killing of OV-infected malignant cells. Existing evidence suggests that the overall effect of NK cells against OV is context dependent. In the past decade, the understanding of cancer and OV biology has improved significantly, which helped refine this class of treatments in early-phase clinical trials. In this review, we summarised different strategies that have been evaluated to modulate NK activities for improving OV therapeutic benefits. Further development of OVs will require a systematic approach to overcome the challenges of the production and delivery of complex gene and cell-based therapies in clinical settings. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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25 pages, 1053 KiB  
Review
Oncolytic Viruses for Malignant Glioma: On the Verge of Success?
by Yogesh R. Suryawanshi and Autumn J. Schulze
Viruses 2021, 13(7), 1294; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071294 - 02 Jul 2021
Cited by 24 | Viewed by 4976
Abstract
Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success [...] Read more.
Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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29 pages, 1732 KiB  
Review
Combinatorial Approaches for Cancer Treatment Using Oncolytic Viruses: Projecting the Perspectives through Clinical Trials Outcomes
by Alexander Malogolovkin, Nizami Gasanov, Alexander Egorov, Marianna Weener, Roman Ivanov and Alexander Karabelsky
Viruses 2021, 13(7), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071271 - 29 Jun 2021
Cited by 31 | Viewed by 4989
Abstract
Recent cancer immunotherapy breakthroughs have fundamentally changed oncology and revived the fading hope for a cancer cure. The immune checkpoint inhibitors (ICI) became an indispensable tool for the treatment of many malignant tumors. Alongside ICI, the application of oncolytic viruses in clinical trials [...] Read more.
Recent cancer immunotherapy breakthroughs have fundamentally changed oncology and revived the fading hope for a cancer cure. The immune checkpoint inhibitors (ICI) became an indispensable tool for the treatment of many malignant tumors. Alongside ICI, the application of oncolytic viruses in clinical trials is demonstrating encouraging outcomes. Dozens of combinations of oncolytic viruses with conventional radiotherapy and chemotherapy are widely used or studied, but it seems quite complicated to highlight the most effective combinations. Our review summarizes the results of clinical trials evaluating oncolytic viruses with or without genetic alterations in combination with immune checkpoint blockade, cytokines, antigens and other oncolytic viruses as well. This review is focused on the efficacy and safety of virotherapy and the most promising combinations based on the published clinical data, rather than presenting all oncolytic virus variations, which are discussed in comprehensive literature reviews. We briefly revise the research landscape of oncolytic viruses and discuss future perspectives in virus immunotherapy, in order to provide an insight for novel strategies of cancer treatment. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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16 pages, 678 KiB  
Review
The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment
by Ifeanyi Kingsley Uche, Konstantin G. Kousoulas and Paul J. F. Rider
Viruses 2021, 13(7), 1200; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071200 - 22 Jun 2021
Cited by 13 | Viewed by 3891
Abstract
The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, [...] Read more.
The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment. Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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15 pages, 1167 KiB  
Review
Oncolytic Virotherapy Treatment of Breast Cancer: Barriers and Recent Advances
by Amy Kwan, Natalie Winder and Munitta Muthana
Viruses 2021, 13(6), 1128; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061128 - 11 Jun 2021
Cited by 12 | Viewed by 3485
Abstract
Oncolytic virotherapy (OV) is an emerging class of immunotherapeutic drugs. Their mechanism of action is two-fold: direct cell lysis and unmasking of the cancer through immunogenic cell death, which allows the immune system to recognize and eradicate tumours. Breast cancer is the most [...] Read more.
Oncolytic virotherapy (OV) is an emerging class of immunotherapeutic drugs. Their mechanism of action is two-fold: direct cell lysis and unmasking of the cancer through immunogenic cell death, which allows the immune system to recognize and eradicate tumours. Breast cancer is the most common cancer in women and is challenging to treat with immunotherapy modalities because it is classically an immunogenically “cold” tumour type. This provides an attractive niche for OV, given viruses have been shown to turn “cold” tumours “hot,” thereby opening a plethora of treatment opportunities. There has been a number of pre-clinical attempts to explore the use of OV in breast cancer; however, these have not led to any meaningful clinical trials. This review considers both the potential and the barriers to OV in breast cancer, namely, the limitations of monotherapy and the scope for combination therapy, improving viral delivery and challenges specific to the breast cancer population (e.g., tumour subtype, menopausal status, age). Full article
(This article belongs to the Special Issue Oncolytic Viruses Therapy)
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