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Oncolytic Viruses: New Cancer Immunotherapy Drugs
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Oncolytic Viruses: New Cancer Immunotherapy Drugs

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (25 April 2025) | Viewed by 7214

Special Issue Editor

Dr. Nikolas T. Martin

E-Mail Website
Guest Editor
The Ottawa Hospital Research Institute, Biotherapeutics Manufacturing Centre, Virus Manufacturing Facility, Ottawa, ON, Canada
Interests: oncolytic virotherapy; immunology; immunotherapy; viral vectors

Special Issue Information

Dear Colleagues,

The COVID-19 pandemic has illuminated the power, speed, and adaptability of one of our oldest foes—viruses. Despite the devastating impact of these pathogens, we have been able to harness their abilities to our own advantage and to make them our allies in the fight against the deadly disease that is cancer. The introduction of more advanced gene-editing methods combined with an ever-increasing understanding of both tumor immunology and virology facilitated the development of a new class of anti-cancer therapeutics, known as oncolytic viruses. Despite their name, these viruses do not rely solely on their lytic potential. Several years of research have shown that the interplay of these recombinant viruses and the tumor-microenvironment is much more complex than we initially thought. Instead of being a purely lytic agent, oncolytic viruses can act more as immune modulators, alerting the patient’s immune system to the presence of malignant neoplasms, and thus are able to turn the infamous immunologically “cold” tumor microenvironment into a “hot” one. This can be achieved by clever design and by combining findings from the fields of oncology, immunology, and virology. Research groups around the world are developing novel, advanced, and modified virus platforms, encoding arrays of heterologous proteins and non-coding RNAs, often in combination with modulated expression systems. Combined with a wide variety of available oncolytic virus platforms, originating from the families of Adenoviruses, Herpesviruses, Poxviruses, Rhabdoviruses, and Paramyxoviruses, to name a few, there is an almost infinite field of research on this family of anti-cancer immunotherapy drugs. It is with great pleasure that we showcase a small selection of these advanced technologies developed in this Special Issue on oncolytic viruses.

Dr. Nikolas T. Martin
Guest Editor

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Published Papers (5 papers)

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Research

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16 pages, 6091 KiB  
Article
Sindbis Virus Platform Provides an Oncolytic-Virus-Mediated and Immunotherapeutic Strategy to Overcome the Challenging Microenvironment of Pancreatic Cancer
by Silvana Opp, Christine Pampeno, Alicia Hurtado and Daniel Meruelo
Pharmaceuticals 2025, 18(5), 725; https://doi.org/10.3390/ph18050725 - 15 May 2025
Viewed by 198
Abstract
Background/Objectives: Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of several types of cancers. In this study, we assess treatment efficacy for metastatic and immunosuppressive pancreatic cancer. Methods: Orthotopic mouse models were generated by injection of tumor cells [...] Read more.
Background/Objectives: Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of several types of cancers. In this study, we assess treatment efficacy for metastatic and immunosuppressive pancreatic cancer. Methods: Orthotopic mouse models were generated by injection of tumor cells into the pancreatic parenchyma. Sindbis vectors were inoculated intraperitoneally. Imaging of tumors was performed by either MRI or in vivo imaging using luciferase. Flow cytometry, multi-immunofluorescence and elispot analysis were performed for certain tumors. Results: SV can infect and reduce pancreatic tumors in three mouse model systems: a model bearing human pancreatic tumors, a highly metastatic model, and a model that reflects the highly immunosuppressive, desmoplastic microenvironment common to human pancreatic cancer. Conclusions: Combination of SV vector expressing IL12 with an immune co-stimulatory agent, anti-OX40, can reduce tumors, facilitate an influx of immune response cells into the tumor microenvironment, and prevent tumors in mice rechallenged with tumor cells promising an effective treatment for pancreatic cancer. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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18 pages, 39366 KiB  
Article
RNAi Screening in Tumor Cells Identifies Artificial microRNAs That Improve Oncolytic Virus Replication
by Hannah Klemets, Angelina Bardoul, Adrian Pelin, Ragunath Singaravelu, Meaghan Boileau, Theresa Falls, Julia Petryk, Marie-Claude Bourgeois-Daigneault, John C. Bell and Dominic G. Roy
Pharmaceuticals 2025, 18(5), 708; https://doi.org/10.3390/ph18050708 - 10 May 2025
Viewed by 282
Abstract
Background/Objectives: Oncolytic viruses infect and kill tumor cells while leaving normal cells unharmed. They are often attenuated through the reduction in their ability to antagonize antiviral defenses, leading to robust replication in tumor cells, which often possess defects in antiviral pathways, while [...] Read more.
Background/Objectives: Oncolytic viruses infect and kill tumor cells while leaving normal cells unharmed. They are often attenuated through the reduction in their ability to antagonize antiviral defenses, leading to robust replication in tumor cells, which often possess defects in antiviral pathways, while minimizing replication in normal cells. However, not all tumors have defects in their antiviral defenses, and virus replication in these tumors is minimal, thus limiting therapeutic benefits. Therefore, identifying and modulating host factors that regulate virus replication in oncolytic virus-resistant cancer cells, but not normal cells, could lead to increased replication in these tumors and potentially improved therapeutic outcomes. Methods: To identify host factors that modulate oncolytic virus replication in tumor cells, we conducted an RNA interference screen by using a replication-competent library of Sindbis virus recombinants individually enabled with the capacity to elicit RNA interference in host genes via the expression of artificial microRNAs. Since the expression of artificial microRNAs is coupled to virus replication, this results in the selective enrichment of viral clones which express an artificial microRNA that promotes virus replication. Results: By using this approach, the serial passage of the Sindbis virus–artificial microRNA library in a tumor cell line followed by the deep sequencing of the selected viral populations led to the identification of several artificial microRNA sequences that were enriched. Furthermore, the identified artificial miRNA sequences increased the replication of several oncolytic viruses both in vitro and in vivo, ultimately leading to an enhanced therapeutic effect. Conclusions: Altogether, our study highlights the utility of this screening platform in identifying artificial microRNAs that enhance oncolytic virus efficacy. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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13 pages, 4472 KiB  
Article
The Small GTPase Ran Increases Sensitivity of Ovarian Cancer Cells to Oncolytic Vesicular Stomatitis Virus
by Karen Geoffroy, Mélissa Viens, Emma Mary Kalin, Zied Boudhraa, Dominic Guy Roy, Jian Hui Wu, Diane Provencher, Anne-Marie Mes-Masson and Marie-Claude Bourgeois-Daigneault
Pharmaceuticals 2024, 17(12), 1662; https://doi.org/10.3390/ph17121662 - 10 Dec 2024
Viewed by 1022
Abstract
Background/Objectives: Ovarian cancer is the deadliest gynecologic cancer, and with the majority of patients dying within the first five years of diagnosis, new therapeutic options are required. The small guanosine triphosphatase (GTPase) Ras-related nuclear protein (Ran) has been reported to be highly expressed [...] Read more.
Background/Objectives: Ovarian cancer is the deadliest gynecologic cancer, and with the majority of patients dying within the first five years of diagnosis, new therapeutic options are required. The small guanosine triphosphatase (GTPase) Ras-related nuclear protein (Ran) has been reported to be highly expressed in high-grade serous ovarian cancers (HGSOCs) and associated with poor outcomes. Blocking Ran function or preventing its expression were shown to be promising treatment strategies, however, there are currently no small molecule inhibitors available to specifically inhibit Ran function. Interestingly, a previous study suggested that the Vesicular stomatitis virus (VSV) could inhibit Ran activity. Given that VSV is an oncolytic virus (OV) and, therefore, has anti-cancer activity, we reasoned that oncolytic VSV (oVSV) might be particularly effective against ovarian cancer via Ran inhibition. Methods: We evaluated the sensitivity of patient-derived ovarian cancer cell lines to oVSV, as well as the impact of oVSV on Ran and vice versa, using overexpression systems, small interfering RNAs (siRNAs), and drug inhibition. Results: In this study, we evaluated the interplay between oVSV and Ran and found that, although oVSV does not consistently block Ran, increased Ran activation allows for better oVSV replication and tumor cell killing. Conclusions: Our study reveals a positive impact of Ran on oVSV sensitivity. Given the high expression of Ran in HGSOCs, which are particularly aggressive ovarian cancers, our data suggest that oVSV could be effective against the deadliest form of the disease. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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13 pages, 5956 KiB  
Article
Cytocidal Effect of Irradiation on Gastric Cancer Cells Infected with a Recombinant Mammalian Orthoreovirus Expressing a Membrane-Targeted KillerRed
by Yoshinori Shirasaka, Kentaro Yamada, Tsuyoshi Etoh, Kazuko Noguchi, Takumi Hasegawa, Katsuhiro Ogawa, Takeshi Kobayashi, Akira Nishizono and Masafumi Inomata
Pharmaceuticals 2024, 17(1), 79; https://doi.org/10.3390/ph17010079 - 8 Jan 2024
Cited by 1 | Viewed by 2214
Abstract
The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic virus and photodynamic therapy can be one of the promising modalities to overcome this. Mammalian orthoreovirus (MRV) is an [...] Read more.
The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic virus and photodynamic therapy can be one of the promising modalities to overcome this. Mammalian orthoreovirus (MRV) is an oncolytic virus that has been used in clinical trials for several cancers. In this study, we developed and evaluated a recombinant MRV strain type 3 Dearing (T3D) that expresses membrane-targeting KillerRed (KRmem), a phototoxic fluorescent protein that produces cytotoxic reactive oxygen species upon light irradiation. KRmem was fused in-frame to the 3′ end of the σ2 viral gene in the S2 segment using a 2A peptide linker, enabling the expression of multiple proteins from a single transcript. RNA electrophoresis, Western blotting, and immunofluorescence analyses confirmed functional insertion of KRmem into the recombinant virus. The growth activity of the recombinant virus was comparable to that of the wild-type MRV in a cultured cell line. The recombinant virus infected two GC cell lines (MKN45P and MKN7), and a significant cytocidal effect was observed in MKN45P cells infected with the recombinant virus after light irradiation. Thus, recombinant MRV-expressing KRmem has the potential to serve as a novel treatment tool for GC. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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Review

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18 pages, 680 KiB  
Review
Where Are We Now with Oncolytic Viruses in Melanoma and Nonmelanoma Skin Malignancies?
by George Nassief, Angela Anaeme, Karen Moussa, David Chen and George Ansstas
Pharmaceuticals 2024, 17(7), 916; https://doi.org/10.3390/ph17070916 - 9 Jul 2024
Viewed by 2606
Abstract
Skin cancer prognosis has greatly improved recently due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients with advanced skin cancer still experience immunotherapy resistance and disease progression during ICI treatment, thus calling for novel therapeutics which address this treatment gap. [...] Read more.
Skin cancer prognosis has greatly improved recently due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients with advanced skin cancer still experience immunotherapy resistance and disease progression during ICI treatment, thus calling for novel therapeutics which address this treatment gap. Talimogene laherparepvec (T-VEC) has gained popularity in recent years as a viable treatment option for patients with skin cancer. In preclinical studies, T-VEC demonstrated both a direct anti-tumor effect in injected lesions as well as a systemic immune-mediated effect in non-injected lesions, which could pose additional benefits when combined with ICI therapy. Following promising results from the OPTiM trial, the Food and Drug Administration (FDA) approved the usage of T-VEC as a single agent in advanced melanoma. However, the MASTERKEY-265 trial demonstrated that adding T-VEC to pembrolizumab did not offer additional clinical benefit in patients with melanoma. Nevertheless, the promising efficacy of T-VEC and its approval by the FDA helped oncolytic viruses (OVs) gain wide attention in cancer therapy, and extensive research has been undertaken to evaluate the usage of OVs in other tumors such as sarcomas and breast cancers. Here, we provide a review of clinical results from 2022 to 2024 that investigate the efficacy and safety of OVs as a monotherapy or in combination with other therapies in skin malignancies. Furthermore, we delineate the current limitations in OV utilization and outline future directions to enhance clinical outcomes for patients with skin malignancies receiving OV-based therapies. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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