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Cancers
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Oncolytic Viruses as Cancer Immunotherapy Agents
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Oncolytic Viruses as Cancer Immunotherapy Agents

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (10 August 2022) | Viewed by 32646

Special Issue Editor

Dr. Masataka Suzuki

E-Mail Website
Guest Editor
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
Interests: oncolytic adenovirus; viro-immunotherapy; CAR cell therapy; checkpoint inhibitor; combination immunotherapy

Special Issue Information

Dear Colleagues, 

The clinical success of immune checkpoint inhibitors (ICIs) refocuses efforts back to leveraging the host immune system to eliminate cancer cells. However, the benefits of ICI therapy remain limited to a subset of patients. It has become clear that successful immunotherapy for advanced cancer needs to target multiple pathways to overcome complexities presented by these tumors. Oncolytic viruses (OVs) selectively replicate in and kill cancer cells either due to natural tumor tropism or genetic manipulation of the wild-type (WT) virus. Since viral infection triggers innate immune responses through various pattern recognition receptors, OVs themselves function as adjuvants, leading to immune stimulation and immune cell infiltration at tumor sites (“Cold” to “Hot” immune status) in addition to induction of immunogenic cell death through oncolysis. This results in the development of adaptive immune responses against cancer cells and the oncolytic virus.

Findings in preclinical and clinical studies indicate that immunostimulation through OV treatment contributes to antitumor effects. Thus, many studies have taken advantage of the transgene capacity of OVs to deliver immunomodulatory molecules to the tumor site to further augment host immune activation, targeting, destruction of tumor stromal components, and prolong immune cell persistence (“Armed” OVs). One “Armed” OV approved for use in the United States and Europe, talimogene laherparepvec (T-VEC), is a herpes simplex virus type 1 (HSV-1)-based OV expressing human GM-CSF to additionally enhance antitumor immune responses.  

Based on recent clinical outcomes with “Armed” OVs (e.g. T-VEC), OV approaches have garnered a lot of scientific and clinical interest as cancer immunotherapy agents. This Special Issue will highlight the current status of OVs undergoing both preclinical and clinical studies. Since durable clinical activity has recently been reported with OVs used in combinatorial approaches (e.g., chemotherapy, checkpoint inhibitor), we will also highlight combination strategies to maximize clinical outcomes using OVs.

Dr. Masataka Suzuki
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 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.

Keywords

  • oncolytic virus
  • viro-immunotherapy
  • antitumor immune response
  • combination therapy with oncolytic virus
  • preclinical model systems
  • cancer immunotherapy

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Published Papers (7 papers)

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Research

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19 pages, 6461 KiB  
Article
HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy
by Amanda Rosewell Shaw, Caroline Porter, Greyson Biegert, Lisa Jatta and Masataka Suzuki
Cancers 2022, 14(11), 2769; https://doi.org/10.3390/cancers14112769 - 2 Jun 2022
Cited by 9 | Viewed by 2468
Abstract
For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses have well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors have been [...] Read more.
For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses have well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors have been generated with reduced or enhanced immunogenicity, depending on their intended purpose, and with increased transgene capacity. The latest-generation Ad vector is the Helper-dependent Ad (HDAd), in which all viral coding sequences are removed from the genome, leaving only the cis-acting ITRs and packaging sequences, providing up to 34 kb of transgene capacity. Although HDAds are replication incompetent, their innate immunogenicity remains intact. Therefore, the HDAd is an ideal cancer gene therapy vector as its infection results in anti-viral immune stimulation that can be enhanced or redirected towards the tumor via transgene expression. Co-infection of tumor cells with an oncolytic Ad and an HDAd results in tumor cell lysis and amplification of HDAd-encoded transgene expression. Here, we describe an HDAd-based cancer gene therapy expressing multiple classes of immunomodulatory molecules to simultaneously stimulate multiple axes of immune pathways: the HydrAd. Overall, the HydrAd platform represents a promising cancer immunotherapy agent against complex solid tumors. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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19 pages, 4106 KiB  
Article
Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma
by Joanna Jazowiecka-Rakus, Aleksander Sochanik, Agata Hadryś, Wojciech Fidyk, Ewa Chmielik, Masmudur M. Rahman and Grant McFadden
Cancers 2022, 14(8), 2022; https://doi.org/10.3390/cancers14082022 - 16 Apr 2022
Cited by 4 | Viewed by 2690
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs) to evaluate murine PDAC [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs) to evaluate murine PDAC treatment in conjunction with gemcitabine (GEM). The cytotoxicity of this treatment was confirmed in vitro using human and murine pancreatic cancer cell cultures, which were more sensitive to the combined approach and largely destroyed. Unlike cancer cells, ADSCs sustain significant viability after infection. The in vivo administration of vMyx-LIGHT-loaded ADSCs and gemcitabine was evaluated using immunocompetent mice with induced orthotopic PDAC lesions. The expression of virus-encoded LIGHT increased the influx of T cells to the tumor site. Shielded virus followed by gemcitabine improved tumor regression and survival. The addition of gemcitabine slightly compromised the adaptive immune response boost obtained with the shielded virus alone, conferring no survival benefit. ADSCs pre-loaded with vMyx-LIGHT allowed the effective transport of the oncolytic construct to PDAC lesions and yielded significant immune response; additional GEM administration failed to improve survival. In view of our results, the delivery of targeted/shielded virus in combination with TGF-β ablation and/or checkpoint inhibitors is a promising option to improve the therapeutic effects of vMyx-LIGHT/ADSCs against PDAC in vivo. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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18 pages, 5083 KiB  
Article
Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma
by John D. Christie, Nicole Appel, Liqiang Zhang, Kenneth Lowe, Jacquelyn Kilbourne, Juliane Daggett-Vondras, Natalie Elliott, Alexandra R. Lucas, Joseph N. Blattman, Masmudur M. Rahman and Grant McFadden
Cancers 2022, 14(2), 337; https://doi.org/10.3390/cancers14020337 - 11 Jan 2022
Cited by 7 | Viewed by 2379
Abstract
Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases [...] Read more.
Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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19 pages, 3628 KiB  
Article
An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma
by Kathleen M. Storey and Trachette L. Jackson
Cancers 2021, 13(21), 5314; https://doi.org/10.3390/cancers13215314 - 22 Oct 2021
Cited by 16 | Viewed by 2890
Abstract
Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as [...] Read more.
Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as the lethal brain tumor glioblastoma (GBM). However, uncertainty remains regarding optimal dosing strategies, including how the spatial location of viral doses impacts therapeutic efficacy and tumor landscape characteristics that are most conducive to producing an effective immune response. We develop a three-dimensional agent-based model (ABM) of GBM undergoing treatment with a combination of an oncolytic Herpes Simplex Virus and an anti-PD-1 immunotherapy. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We utilize the spatially explicit nature of the ABM to determine optimal viral dosing in both the temporal and spatial contexts. After proposing an adaptive viral dosing strategy that chooses to dose sites at the location of highest tumor cell density, we find that, in most cases, this adaptive strategy produces a more effective treatment outcome than repeatedly dosing in the center of the tumor. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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Review

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20 pages, 1851 KiB  
Review
Systems Biology Approaches for the Improvement of Oncolytic Virus-Based Immunotherapies
by Lorella Tripodi, Emanuele Sasso, Sara Feola, Ludovica Coluccino, Maria Vitale, Guido Leoni, Barbara Szomolay, Lucio Pastore and Vincenzo Cerullo
Cancers 2023, 15(4), 1297; https://doi.org/10.3390/cancers15041297 - 17 Feb 2023
Cited by 6 | Viewed by 3097
Abstract
Oncolytic virus (OV)-based immunotherapy is mainly dependent on establishing an efficient cell-mediated antitumor immunity. OV-mediated antitumor immunity elicits a renewed antitumor reactivity, stimulating a T-cell response against tumor-associated antigens (TAAs) and recruiting natural killer cells within the tumor microenvironment (TME). Despite the fact [...] Read more.
Oncolytic virus (OV)-based immunotherapy is mainly dependent on establishing an efficient cell-mediated antitumor immunity. OV-mediated antitumor immunity elicits a renewed antitumor reactivity, stimulating a T-cell response against tumor-associated antigens (TAAs) and recruiting natural killer cells within the tumor microenvironment (TME). Despite the fact that OVs are unspecific cancer vaccine platforms, to further enhance antitumor immunity, it is crucial to identify the potentially immunogenic T-cell restricted TAAs, the main key orchestrators in evoking a specific and durable cytotoxic T-cell response. Today, innovative approaches derived from systems biology are exploited to improve target discovery in several types of cancer and to identify the MHC-I and II restricted peptide repertoire recognized by T-cells. Using specific computation pipelines, it is possible to select the best tumor peptide candidates that can be efficiently vectorized and delivered by numerous OV-based platforms, in order to reinforce anticancer immune responses. Beyond the identification of TAAs, system biology can also support the engineering of OVs with improved oncotropism to reduce toxicity and maintain a sufficient portion of the wild-type virus virulence. Finally, these technologies can also pave the way towards a more rational design of armed OVs where a transgene of interest can be delivered to TME to develop an intratumoral gene therapy to enhance specific immune stimuli. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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22 pages, 674 KiB  
Review
Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers
by Dimitrios C. Ziogas, Anastasios Martinos, Dioni-Pinelopi Petsiou, Amalia Anastasopoulou and Helen Gogas
Cancers 2022, 14(12), 2873; https://doi.org/10.3390/cancers14122873 - 10 Jun 2022
Cited by 5 | Viewed by 2800
Abstract
Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the [...] Read more.
Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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17 pages, 6497 KiB  
Review
Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy
by Masmudur M. Rahman and Grant McFadden
Cancers 2021, 13(21), 5452; https://doi.org/10.3390/cancers13215452 - 29 Oct 2021
Cited by 84 | Viewed by 15206
Abstract
Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a [...] Read more.
Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert “immune-cold” tumors to “immune-hot” will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Immunotherapy Agents)
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