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Cancers
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Oncolytic Virus Therapy Against Cancer
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Oncolytic Virus Therapy Against Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 28899

Special Issue Editor

Dr. Mihnea Bostina

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
Interests: structural biology; picornaviruses; virus entry; viral assembly; oncolytic viruses

Special Issue Information

Dear Colleagues,

Recent developments in research into viruses’ capability to destroy cancer cells have shown that oncolytic virotherapy has the potential to become a sustainable alternative to existing therapies. Using a self-amplifying antitumor agent that selectively replicates in cancer cells and avoids destroying healthy tissue offers obvious therapeutic advantages. Several directions of research are underlying this approach. A number of viruses were shown to pose an intrinsic tumor tropism, making their use straightforward in cancer therapy. However, the modifications of viruses to target specific cancer types significantly expands the arsenal of agents capable of fighting tumors. Research aiming to improve viral anticancer efficacy and to extend the therapeutic potential are major topics in oncolytic virotherapy. Engineering viral constructs or devising new viral formulations capable of escaping the surveillance of the immune system is a continuous undertaking for further development of all oncolytic viruses. A major benefit of the use of viruses is the immunotherapeutic effect associated with infection, and multiple strategies are used to amplify this immune response targeted at cancer cells.

This Special Issue aims to offer an overview of these current progresses made in the development of oncolytic viruses to target various types of cancers.

Dr. Mihnea Bostina
Guest Editor

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

Jump to: Review

17 pages, 4625 KiB  
Article
Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models
by Alvaro Morales-Molina, Miguel Ángel Rodríguez-Milla, Alicia Gimenez-Sanchez, Ana Judith Perisé-Barrios and Javier García-Castro
Cancers 2020, 12(7), 1920; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071920 - 16 Jul 2020
Cited by 13 | Viewed by 3948
Abstract
Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to [...] Read more.
Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)—the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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18 pages, 1817 KiB  
Article
Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy
by Maibritt Kretschmer, Patrycja Kadlubowska, Daniel Hoffmann, Birco Schwalbe, Heidi Auerswald and Michael Schreiber
Cancers 2020, 12(4), 1000; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12041000 - 18 Apr 2020
Cited by 14 | Viewed by 4134
Abstract
Glioblastoma multiforme is the most lethal type of brain tumor that is not yet curable owing to its frequent resurgence after surgery. Resistance is mainly caused by the presence of a subpopulation of tumor cells, the glioma stem cells (GSCs), which are highly [...] Read more.
Glioblastoma multiforme is the most lethal type of brain tumor that is not yet curable owing to its frequent resurgence after surgery. Resistance is mainly caused by the presence of a subpopulation of tumor cells, the glioma stem cells (GSCs), which are highly resistant to radiation and chemotherapy. In 2015, Zikavirus (ZIKV)-induced microcephaly emerged in newborns, indicating that ZIKV has a specific neurotropism. Accordingly, an oncolytic tropism for infecting GSCs was demonstrated in a murine tumor model. Like other flaviviruses, ZIKV is enveloped by two proteins, prM and E. The pME expression plasmid along with the HIV-1 vector pNL Luc AM generated prME pseudotyped viral particles. Four different prME envelopes, Z1 to Z4, were cloned, and the corresponding pseudotypes, Z1- to Z4-HIVluc, produced by this two-plasmid system, were tested for entry efficiency using Vero-B4 cells. The most efficient pseudotype, Z1-HIVluc, also infected glioma-derived cell lines U87 and 86HG39. The pseudotype system was then extended by using a three-plasmid system including pME-Z1, the HIV-1 packaging plasmid psPAX2, and the lentiviral vector pLenti-luciferase-P2A-Neo. The corresponding pseudotype, designated Z1-LENTIluc, also infected U87 and 86HG39 cells. Altogether, a pseudotyped virus especially targeting glioma-derived cells might be a promising candidate for a prospective glioblastoma-directed virotherapy. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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19 pages, 8522 KiB  
Article
Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase
by S. M. Bakhtiar Ul Islam, Bora Lee, Fen Jiang, Eung-Kyun Kim, Soon Cheol Ahn and Tae-Ho Hwang
Cancers 2020, 12(1), 228; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010228 - 17 Jan 2020
Cited by 12 | Viewed by 4430
Abstract
Oncolytic viruses are a promising class of anti-tumor agents; however, concerns regarding uncontrolled viral replication have led to the development of a replication-controllable oncolytic vaccinia virus (OVV). The engineering involves replacing the native thymidine kinase (VV-tk) gene, in a Wyeth strain [...] Read more.
Oncolytic viruses are a promising class of anti-tumor agents; however, concerns regarding uncontrolled viral replication have led to the development of a replication-controllable oncolytic vaccinia virus (OVV). The engineering involves replacing the native thymidine kinase (VV-tk) gene, in a Wyeth strain vaccinia backbone, with the herpes simplex virus thymidine kinase (HSV-tk) gene, which allows for viral replication control via ganciclovir (GCV, an antiviral/cytotoxic pro-drug). Adding the wild-type HSV-tk gene might disrupt the tumor selectivity of VV-tk deleted OVVs; therefore, only engineered viruses that lacked tk activity were selected as candidates. Ultimately, OTS-412, which is an OVV containing a mutant HSV-tk, was chosen for characterization regarding tumor selectivity, sensitivity to GCV, and the influence of GCV on OTS-412 anti-tumor effects. OTS-412 demonstrated comparable replication and cytotoxicity to VVtk- (control, a VV-tk deleted OVV) in multiple cancer cell lines. In HCT 116 mouse models, OTS-412 replication in tumors was reduced by >50% by GCV (p = 0.004); additionally, combination use of GCV did not compromise the anti-tumor effects of OTS-412. This is the first report of OTS-412, a VV-tk deleted OVV containing a mutant HSV-tk transgene, which demonstrates tumor selectivity and sensitivity to GCV. The HSV-tk/GCV combination provides a safety mechanism for future clinical applications of OTS-412. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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Review

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28 pages, 2612 KiB  
Review
Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy
by Olga V. Matveeva and Svetlana A. Shabalina
Cancers 2020, 12(12), 3659; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123659 - 05 Dec 2020
Cited by 6 | Viewed by 3416
Abstract
The effectiveness of oncolytic virotherapy in cancer treatment depends on several factors, including successful virus delivery to the tumor, ability of the virus to enter the target malignant cell, virus replication, and the release of progeny virions from infected cells. The multi-stage process [...] Read more.
The effectiveness of oncolytic virotherapy in cancer treatment depends on several factors, including successful virus delivery to the tumor, ability of the virus to enter the target malignant cell, virus replication, and the release of progeny virions from infected cells. The multi-stage process is influenced by the efficiency with which the virus enters host cells via specific receptors. This review describes natural and artificial receptors for two oncolytic paramyxoviruses, nonpathogenic measles, and Sendai viruses. Cell entry receptors are proteins for measles virus (MV) and sialylated glycans (sialylated glycoproteins or glycolipids/gangliosides) for Sendai virus (SeV). Accumulated published data reviewed here show different levels of expression of cell surface receptors for both viruses in different malignancies. Patients whose tumor cells have low or no expression of receptors for a specific oncolytic virus cannot be successfully treated with the virus. Recent published studies have revealed that an expression signature for immune genes is another important factor that determines the vulnerability of tumor cells to viral infection. In the future, a combination of expression signatures of immune and receptor genes could be used to find a set of oncolytic viruses that are more effective for specific malignancies. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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20 pages, 1293 KiB  
Review
Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges
by Shyambabu Chaurasiya, Yuman Fong and Susanne G. Warner
Cancers 2020, 12(6), 1699; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061699 - 26 Jun 2020
Cited by 28 | Viewed by 5350
Abstract
The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic [...] Read more.
The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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24 pages, 996 KiB  
Review
The Double-Edged Sword Role of Viruses in Gastric Cancer
by Paulina Niedźwiedzka-Rystwej, Ewelina Grywalska, Rafał Hrynkiewicz, Mikołaj Wołącewicz, Rafał Becht and Jacek Roliński
Cancers 2020, 12(6), 1680; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061680 - 24 Jun 2020
Cited by 6 | Viewed by 3218
Abstract
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and [...] Read more.
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and their potential seem to be an important issue. On one hand, several oncogenic viruses have been noticed in the case of gastric cancer, making the positive treatment even more advantageous, but on the other, viruses exist with a potential therapeutic role in this malignancy. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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17 pages, 1870 KiB  
Review
Efficacy and Safety of Oncolytic Viruses in Randomized Controlled Trials: A Systematic Review and Meta-Analysis
by Zengbin Li, Zeju Jiang, Yingxuan Zhang, Xiaotian Huang and Qiong Liu
Cancers 2020, 12(6), 1416; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061416 - 30 May 2020
Cited by 19 | Viewed by 3562
Abstract
Oncolytic virotherapy is a promising antitumor therapeutic strategy. It is based on the ability of viruses to selectively kill cancer cells and induce host antitumor immune responses. However, the clinical outcomes of oncolytic viruses (OVs) vary widely. Therefore, we performed a meta-analysis to [...] Read more.
Oncolytic virotherapy is a promising antitumor therapeutic strategy. It is based on the ability of viruses to selectively kill cancer cells and induce host antitumor immune responses. However, the clinical outcomes of oncolytic viruses (OVs) vary widely. Therefore, we performed a meta-analysis to illustrate the efficacy and safety of oncolytic viruses. The Cochrane Library, PubMed, and EMBASE databases were searched for randomized controlled trials (RCTs) published up to 31 January 2020. The data for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were independently extracted by two investigators from 11 studies that met the inclusion criteria. In subgroup analyses, the objective response rate benefit was observed in patients treated with oncolytic DNA viruses (odds ratio (OR) = 4.05; 95% confidence interval (CI): 1.96–8.33; p = 0.0002), but not in those treated with oncolytic RNA viruses (OR = 1.00, 95% CI: 0.66–1.52, p = 0.99). Moreover, the intratumoral injection arm yielded a statistically significant improvement (OR = 4.05, 95% CI: 1.96–8.33, p = 0.0002), but no such improvement was observed for the intravenous injection arm (OR = 1.00, 95% CI: 0.66–1.52, p = 0.99). Among the five OVs investigated in RCTs, only talimogene laherparepvec (T-VEC) effectively prolonged the OS of patients (hazard ratio (HR), 0.79; 95% CI: 0.63–0.99; p = 0.04). None of the oncolytic virotherapies improved the PFS (HR = 1.00, 95% CI: 0.85–1.19, p = 0.96). Notably, the pooled rate of severe AEs (grade ≥3) was higher for the oncolytic virotherapy group (39%) compared with the control group (27%) (risk difference (RD), 12%; risk ratio (RR), 1.44; 95% CI: 1.17–1.78; p = 0.0006). This review offers a reference for fundamental research and clinical treatment of oncolytic viruses. Further randomized controlled trials are needed to verify these results. Full article
(This article belongs to the Special Issue Oncolytic Virus Therapy Against Cancer)
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