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Viruses
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Oncolytic HSVs
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Oncolytic HSVs

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 (15 June 2021) | Viewed by 26076

Special Issue Editors

Prof. Dr. Gabriella Campadelli-Fiume

E-Mail Website
Guest Editor
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Interests: Virology; oncolytic HSV; retargeted virus
Dr. Andrea Vannini

E-Mail Website
Guest Editor
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Interests: Virology; oncolytic HSV; retargeted virus

Special Issue Information

Dear Colleagues,

Several series of events led to the evolution of herpes simplex virus (HSV) from a human pathogen to a promising onco-immunotherapeutic agent. These were the development of techniques for insertion or deletion of genes from HSV DNA, the discovery of the γ134.5 gene, the finding that γ134.5 deletion mutants replicated readily in cultured cells but were virtually apathogenic in experimental animals, and the discovery that such mutants replicated in and destroyed tumors. The discovery that mutants lacking other HSV genes also expressed oncolytic functions soon followed. Equally important, HSV DNA tolerates the expression of non viral genes inserted into the HSV genome.

Research on oHSV literally exploded after the licensing of oHSV OncoVexGM-CSF by FDA and EMA for the treatment of melanoma. The key discoveries in various stages of development are that insertion into the HSV genome of intact or modified cellular gene may alter susceptibility to infection, enhance affinity of oHSV for specific tumors, and increase the host immune response to tumor.

The oHSV research and development is expanding very rapidly in many different directions but its goals remain unchanged: to develop oHSV as a premier therapeutic for human cancer. This goal would benefit from a review of its accomplishments and directions of its research. In this Special Issue, emphasis will be placed on the diversity of approaches to a common goal: develop HSV as a premier vector of anti-cancer and immunotherapeutic molecules to the site where it is needed most. You are cordially invited to contribute unique research or review articles on this topic.

Prof. Dr. Gabriella Campadelli-Fiume
Dr. Andrea Vannini
Guest Editors

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Keywords

  • herpes simplex virus
  • cancer therapy
  • cancer virotherapy
  • oncolytic virus
  • oncolytic immunotherapy
  • oHSV
  • immunomodulatory molecules
  • cytokine
  • chemokine
  • tumor microenvironment
  • checkpoint inhibitor
  • PD-1
  • PD-L1
  • CTLA-4
  • combination therapy
  • systemic delivery
  • pro-inflammatory cytokines

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Published Papers (7 papers)

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Research

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22 pages, 7086 KiB  
Article
Towards a Precision Medicine Approach and In Situ Vaccination against Prostate Cancer by PSMA-Retargeted oHSV
by Andrea Vannini, Federico Parenti, Daniela Bressanin, Catia Barboni, Anna Zaghini, Gabriella Campadelli-Fiume and Tatiana Gianni
Viruses 2021, 13(10), 2085; https://doi.org/10.3390/v13102085 - 16 Oct 2021
Cited by 3 | Viewed by 2646
Abstract
Prostate specific membrane antigen (PSMA) is a specific high frequency cell surface marker of prostate cancers. Theranostic approaches targeting PSMA show no major adverse effects and rule out off-tumor toxicity. A PSMA-retargeted oHSV (R-405) was generated which both infected and was cytotoxic exclusively [...] Read more.
Prostate specific membrane antigen (PSMA) is a specific high frequency cell surface marker of prostate cancers. Theranostic approaches targeting PSMA show no major adverse effects and rule out off-tumor toxicity. A PSMA-retargeted oHSV (R-405) was generated which both infected and was cytotoxic exclusively for PSMA-positive cells, including human prostate cancer LNCaP and 22Rv1 cells, and spared PSMA-negative cells. R-405 in vivo efficacy against LLC1-PSMA and Renca-PSMA tumors consisted of inhibiting primary tumor growth, establishing long-term T immune response, immune heating of the microenvironment, de-repression of the anti-tumor immune phenotype, and sensitization to checkpoint blockade. The in situ vaccination protected from distant challenge tumors, both PSMA-positive and PSMA-negative, implying that it was addressed also to LLC1 tumor antigens. PSMA-retargeted oHSVs are a precision medicine tool worth being additionally investigated in the immunotherapeutic and in situ vaccination landscape against prostate cancers. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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13 pages, 8348 KiB  
Article
Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus with MEK Inhibitor Trametinib in Some BRAF or KRAS-Mutated Colorectal or Lung Carcinoma Models
by XuSha Zhou, Jing Zhao, Jian V. Zhang, Yinglin Wu, Lei Wang, Xiaoqing Chen, Dongmei Ji and Grace Guoying Zhou
Viruses 2021, 13(9), 1758; https://doi.org/10.3390/v13091758 - 3 Sep 2021
Cited by 7 | Viewed by 3268
Abstract
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated [...] Read more.
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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18 pages, 2947 KiB  
Article
Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted oHSV
by Tatiana Gianni, Valerio Leoni, Mara Sanapo, Federico Parenti, Daniela Bressanin, Catia Barboni, Anna Zaghini, Gabriella Campadelli-Fiume and Andrea Vannini
Viruses 2021, 13(9), 1747; https://doi.org/10.3390/v13091747 - 1 Sep 2021
Cited by 7 | Viewed by 3348
Abstract
We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor [...] Read more.
We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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13 pages, 4066 KiB  
Article
Specificity, Safety, Efficacy of EGFRvIII-Retargeted Oncolytic HSV for Xenotransplanted Human Glioblastoma
by Irene Appolloni, Francesco Alessandrini, Laura Menotti, Elisa Avitabile, Daniela Marubbi, Noemi Piga, Davide Ceresa, Francesca Piaggio, Gabriella Campadelli-Fiume and Paolo Malatesta
Viruses 2021, 13(9), 1677; https://doi.org/10.3390/v13091677 - 24 Aug 2021
Cited by 7 | Viewed by 2512
Abstract
Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across [...] Read more.
Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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Review

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27 pages, 2965 KiB  
Review
In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV
by Nusrat Jahan, Shanawaz M. Ghouse, Robert L. Martuza and Samuel D. Rabkin
Viruses 2021, 13(9), 1740; https://doi.org/10.3390/v13091740 - 31 Aug 2021
Cited by 25 | Viewed by 5000
Abstract
Herpes simplex virus (HSV) can be genetically altered to acquire oncolytic properties so that oncolytic HSV (oHSV) preferentially replicates in and kills cancer cells, while sparing normal cells, and inducing anti-tumor immune responses. Over the last three decades, a better understanding of HSV [...] Read more.
Herpes simplex virus (HSV) can be genetically altered to acquire oncolytic properties so that oncolytic HSV (oHSV) preferentially replicates in and kills cancer cells, while sparing normal cells, and inducing anti-tumor immune responses. Over the last three decades, a better understanding of HSV genes and functions, and improved genetic-engineering techniques led to the development of oHSV as a novel immunovirotherapy. The concept of in situ cancer vaccination (ISCV) was first introduced when oHSV was found to induce a specific systemic anti-tumor immune response with an abscopal effect on non-injected tumors, in the process of directly killing tumor cells. Thus, the use of oHSV for tumor vaccination in situ is antigen-agnostic. The research and development of oHSVs have moved rapidly, with the field of oncolytic viruses invigorated by the FDA/EMA approval of oHSV talimogene laherparepvec in 2015 for the treatment of advanced melanoma. Immunovirotherapy can be enhanced by arming oHSV with immunomodulatory transgenes and/or using them in combination with other chemotherapeutic and immunotherapeutic agents. This review offers an overview of the development of oHSV as an agent for ISCV against solid tumors, describing the multitude of different oHSVs and their efficacy in immunocompetent mouse models and in clinical trials. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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16 pages, 1178 KiB  
Review
Oncolytic HSV: Underpinnings of Tumor Susceptibility
by Chase Kangas, Eric Krawczyk and Bin He
Viruses 2021, 13(7), 1408; https://doi.org/10.3390/v13071408 - 20 Jul 2021
Cited by 8 | Viewed by 3941
Abstract
Oncolytic herpes simplex virus (oHSV) is a therapeutic modality that has seen substantial success for the treatment of cancer, though much remains to be improved. Commonly attenuated through the deletion or alteration of the γ134.5 neurovirulence gene, the basis for the [...] Read more.
Oncolytic herpes simplex virus (oHSV) is a therapeutic modality that has seen substantial success for the treatment of cancer, though much remains to be improved. Commonly attenuated through the deletion or alteration of the γ134.5 neurovirulence gene, the basis for the success of oHSV relies in part on the malignant silencing of cellular pathways critical for limiting these viruses in healthy host tissue. However, only recently have the molecular mechanisms underlying the success of these treatments begun to emerge. Further clarification of these mechanisms can strengthen rational design approaches to develop the next generation of oHSV. Herein, we review our current understanding of the molecular basis for tumor susceptibility to γ134.5-attenuated oHSV, with particular focus on the malignant suppression of nucleic acid sensing, along with strategies meant to improve the clinical efficacy of these therapeutic viruses. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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7 pages, 229 KiB  
Review
The Current Landscape of Oncolytic Herpes Simplex Viruses as Novel Therapies for Brain Malignancies
by Joshua D. Bernstock, Samantha E. Hoffman, Jason A. Chen, Saksham Gupta, Ari D. Kappel, Timothy R. Smith and E. Antonio Chiocca
Viruses 2021, 13(6), 1158; https://doi.org/10.3390/v13061158 - 17 Jun 2021
Cited by 19 | Viewed by 4246
Abstract
Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy [...] Read more.
Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy and, in particular, immunovirotherapy are at the forefront amongst novel therapeutic strategies that are currently under investigation for incurable brain tumors. Accordingly, herein, we provide a focused mini review of pertinent oncolytic herpes viruses (oHSV) that are being investigated in clinical trials. Full article
(This article belongs to the Special Issue Oncolytic HSVs)
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