Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 15137

Special Issue Editors

Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
Interests: oncolytic virus; cancer immunotherapy; oncolytic vaccine; therapeutic cancer vaccine; viro-immunotherapy; immunovirotherapy; gene therapy; vaccinia virus
Special Issues, Collections and Topics in MDPI journals
1. The UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
2. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Interests: oncolytic virus; cancer immunotherapy; oncolytic vaccine; therapeutic cancer vaccine; viro-immunotherapy; immunovirotherapy; gene therapy; vaccinia virus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Four years ago, we successfully launched the Special Issue, “Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer”, which mainly focused on oncolytic viruses (OVs) and their induced antitumor immunity for cancer immunotherapy. In that Special Issue, 25 papers, including 7 original research articles, were published. Building on that, we are launching a third Special Issue.

The oncolytic virus (OV) has emerged as a novel form of immunotherapy for cancer. In the last few years, investigators started to realize that antitumor activity beyond direct oncolysis is also a key contributor to therapeutic efficacy. OV-induced antitumor immunity plays an important, sometimes essential, role in OV-mediated therapeutics for cancer. One particular property of oncolytic viruses worth mentioning is their turning of cold tumors into hot. This unique property makes OV a highly useful agent in combinatorial approaches for cancer immunotherapy.

We cordially invite authors in the field to submit original research or review articles pertaining to this important and fast-progressing field of biomedicine. In particular, articles describing research with combinatorial approaches are strongly encouraged.

Dr. David L. Bartlett
Dr. Zong Sheng Guo
Guest Editors

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Keywords

  • oncolytic virus
  • antitumor immunity
  • tumor antigen
  • cancer vaccine
  • oncolytic vaccine
  • immunotherapy
  • viro-immunotherapy
  • combinatorial therapy
  • immune checkpoint blockade

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Published Papers (6 papers)

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Research

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19 pages, 3052 KiB  
Article
In Vivo Tracking for Oncolytic Adenovirus Interactions with Liver Cells
Biomedicines 2022, 10(7), 1697; https://doi.org/10.3390/biomedicines10071697 - 13 Jul 2022
Cited by 3 | Viewed by 1664
Abstract
Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, [...] Read more.
Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, the complex interplay between Ad and liver cells is not fully understood. Here, by using intravital microscopy, we aimed to follow the infection and immune response in mouse liver from the first minutes up to 72 h post intravenous injection of three Ads carrying delta-24 modification (Ad5-RGD, Ad5/3, and Ad5/35). At 15–30 min following the infusion of Ad5-RGD and Ad5/3 (but not Ad5/35), the virus-bound macrophages demonstrated signs of zeiosis: the formation of long-extended protrusions and dynamic membrane blebbing with the virus release into the blood in the membrane-associated vesicles. Although real-time imaging revealed interactions between the neutrophils and virus-bound KCs within minutes after treatment, and long-term contacts of CD8+ T cells with transduced hepatocytes at 24–72 h, depletion of neutrophils and CD8+ T cells affected neither rate nor dynamics of liver infection. Ad5-RGD failed to complete replicative cycle in hepatocytes, and transduced cells remained impermeable for propidium iodide, with a small fraction undergoing spontaneous apoptosis. In Ad5-RGD-immune mice, the virus neither killed KCs nor transduced hepatocytes, while in the setting of hepatic regeneration, Ad5-RGD enhanced liver transduction. The clinical and biochemical signs of hepatotoxicity correlated well with KC death, but not hepatocyte transduction. Real-time in vivo tracking for dynamic interactions between virus and host cells provides a better understanding of mechanisms underlying Ad-related hepatotoxicity. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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16 pages, 2459 KiB  
Article
Ferroptosis Inducer Improves the Efficacy of Oncolytic Virus-Mediated Cancer Immunotherapy
Biomedicines 2022, 10(6), 1425; https://doi.org/10.3390/biomedicines10061425 - 15 Jun 2022
Cited by 11 | Viewed by 3130
Abstract
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. In this study, we explore the combination of a ferroptosis activator with an oncolytic vaccinia virus in tumor models. Erastin induced cell death in [...] Read more.
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. In this study, we explore the combination of a ferroptosis activator with an oncolytic vaccinia virus in tumor models. Erastin induced cell death in hepatoma, colon, and ovarian cancer cells, but not in melanoma cancer cells. Erastin, not the oncolytic vaccinia virus (OVV), induced the expression of key marker genes for ferroptosis in cancer cells. In hepatocellular carcinoma and colon cancer models, either erastin or OVV inhibited tumor growth, but a combination of the two yielded the best therapeutic effects, as indicated by inhibited tumor growth or regression and longer host survival. Immunological analyses indicate that erastin alone had little or no effect on systemic immunity or local immunity in the tumor. However, when combined with OV, erastin enhanced the number of activated dendritic cells and the activity of tumor-infiltrating T lymphocytes as indicated by an increase in IFN-γ+CD8+ and PD-1+CD8+ T cells. These results demonstrate that erastin can exert cytotoxicity on cancer cells via ferroptosis, but has little effect on immune activity by itself. However, when combined with an OVV, erastin promoted antitumoral immunity and efficacy by increasing the number of activated dendritic cells and promoting the activities of tumor specific CD8+ T cells in the tumor. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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16 pages, 4060 KiB  
Article
Oncolytic Vaccinia Virus Augments T Cell Factor 1-Positive Stem-like CD8+ T Cells, Which Underlies the Efficacy of Anti-PD-1 Combination Immunotherapy
Biomedicines 2022, 10(4), 805; https://doi.org/10.3390/biomedicines10040805 - 30 Mar 2022
Cited by 5 | Viewed by 2161
Abstract
Oncolytic virotherapy has garnered attention as an antigen-agnostic therapeutic cancer vaccine that induces cancer-specific T cell responses without additional antigen loading. As anticancer immune responses are compromised by a lack of antigenicity and chronic immunosuppressive microenvironments, an effective immuno-oncology modality that converts cold [...] Read more.
Oncolytic virotherapy has garnered attention as an antigen-agnostic therapeutic cancer vaccine that induces cancer-specific T cell responses without additional antigen loading. As anticancer immune responses are compromised by a lack of antigenicity and chronic immunosuppressive microenvironments, an effective immuno-oncology modality that converts cold tumors into hot tumors is crucial. To evaluate the immune-activating characteristics of oncolytic vaccinia virus (VACV; JX-594, pexastimogene devacirepvec), diverse murine syngeneic cancer models with different tissue types and immune microenvironments were used. Intratumorally administered mJX-594, a murine variant of JX-594, potently increased CD8+ T cells, including antigen-specific cancer CD8+ T cells, and decreased immunosuppressive cells irrespective of tissue type or therapeutic efficacy. Remodeling of tumors into inflamed ones by mJX-594 led to a response to combined anti-PD-1 treatment, but not to mJX-594 or anti-PD-1 monotherapy. mJX-594 treatment increased T cell factor 1-positive stem-like T cells among cancer-specific CD8+ T cells, and anti-PD-1 combination treatment further increased proliferation of these cells, which was important for therapeutic efficacy. The presence of functional cancer-specific CD8+ T cells in the spleen and bone marrow for an extended period, which proliferated upon encountering cancer antigen-loaded splenic dendritic cells, further indicated that long-term durable anticancer immunity was elicited by oncolytic VACV. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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16 pages, 4008 KiB  
Article
Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment
Biomedicines 2022, 10(1), 173; https://doi.org/10.3390/biomedicines10010173 - 14 Jan 2022
Cited by 4 | Viewed by 2575
Abstract
Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection [...] Read more.
Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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14 pages, 3303 KiB  
Article
Efficient Selection of Recombinant Fluorescent Vaccinia Virus Strains and Rapid Virus Titer Determination by Using a Multi-Well Plate Imaging System
Biomedicines 2021, 9(8), 1032; https://doi.org/10.3390/biomedicines9081032 - 18 Aug 2021
Cited by 4 | Viewed by 2862
Abstract
Engineered vaccinia virus (VACV) strains are used extensively as vectors for the development of novel cancer vaccines and cancer therapeutics. In this study, we describe for the first time a high-throughput approach for both fluorescent rVACV generation and rapid viral titer measurement with [...] Read more.
Engineered vaccinia virus (VACV) strains are used extensively as vectors for the development of novel cancer vaccines and cancer therapeutics. In this study, we describe for the first time a high-throughput approach for both fluorescent rVACV generation and rapid viral titer measurement with the multi-well plate imaging system, IncuCyte®S3. The isolation of a single, well-defined plaque is critical for the generation of novel recombinant vaccinia virus (rVACV) strains. Unfortunately, current methods of rVACV engineering via plaque isolation are time-consuming and laborious. Here, we present a modified fluorescent viral plaque screening and selection strategy that allows one to generally obtain novel fluorescent rVACV strains in six days, with a minimum of just four days. The standard plaque assay requires chemicals for fixing and staining cells. Manual plaque counting based on visual inspection of the cell culture plates is time-consuming. Here, we developed a fluorescence-based plaque assay for quantifying the vaccinia virus that does not require a cell staining step. This approach is less toxic to researchers and is reproducible; it is thus an improvement over the traditional assay. Lastly, plaque counting by virtue of a fluorescence-based image is very convenient, as it can be performed directly on the computer. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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Review

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13 pages, 1021 KiB  
Review
Alphaviruses in Immunotherapy and Anticancer Therapy
Biomedicines 2022, 10(9), 2263; https://doi.org/10.3390/biomedicines10092263 - 13 Sep 2022
Cited by 4 | Viewed by 1729
Abstract
Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA [...] Read more.
Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved. Full article
(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer III)
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