Biomedicines

Editorial

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5 pages, 477 KiB

Open AccessEditorial

Oncolytic Virus Immunotherapy: Showcasing Impressive Progress in Special Issue II

by Zong-Sheng Guo

Biomedicines 2021, 9(6), 663; https://doi.org/10.3390/biomedicines9060663 - 10 Jun 2021

Cited by 3 | Viewed by 2544

Abstract

Cancer immunotherapy has recently become the most promising strategy for hard-to-treat, advanced-stage malignancies [...] Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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Open AccessEditorial

Editorial of the Special Issue: Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer

by Zong Sheng Guo and David L. Bartlett

Biomedicines 2017, 5(3), 52; https://doi.org/10.3390/biomedicines5030052 - 24 Aug 2017

Cited by 6 | Viewed by 4167

Abstract

Oncolytic viruses (OVs), either occurring naturally or through genetic engineering, can selectively infect, replicate in, and kill cancer cells, while leaving normal cells (almost) unharmed [...] Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

Research

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15 pages, 5606 KiB

Open AccessArticle

Oncolytic Adenovirus CD55-Smad4 Suppresses Cell Proliferation, Metastasis, and Tumor Stemness in Colorectal Cancer by Regulating Wnt/β-Catenin Signaling Pathway

by Boduan Xiao, Leilei Zhang, Huihui Liu, Huiling Fang, Chunming Wang, Biao Huang, Xinyuan Liu, Xiumei Zhou and Yigang Wang

Biomedicines 2020, 8(12), 593; https://doi.org/10.3390/biomedicines8120593 - 11 Dec 2020

Cited by 13 | Viewed by 2523

Abstract

During the past few decades, colorectal cancer (CRC) incidence and mortality have significantly increased, and CRC has become the leading cause of cancer-related death worldwide. Thus, exploring novel effective therapies for CRC is imperative. In this study, we investigated the effect of oncolytic [...] Read more.

During the past few decades, colorectal cancer (CRC) incidence and mortality have significantly increased, and CRC has become the leading cause of cancer-related death worldwide. Thus, exploring novel effective therapies for CRC is imperative. In this study, we investigated the effect of oncolytic adenovirus CD55-Smad4 on CRC cell growth. Cell viability assay, animal experiments, flow cytometric analysis, cell migration, and invasion assays, and Western blotting were used to detect the proliferation, apoptosis, migration, and invasion of CRC cells. The oncolytic adenovirus CD55-Smad4 was successfully constructed and effectively suppressed CRC cell proliferation in vivo and in vitro. Notably, CD55-Smad4 activated the caspase signaling pathway, inducing the apoptosis of CRC cells. Additionally, the generated oncolytic adenovirus significantly suppressed migration and invasion of CRC cells by overexpressing Smad4 and inhibiting Wnt/β-catenin/epithelial-mesenchymal transition (EMT) signaling pathway. Moreover, CRC cells treated with CD55-Smad4 formed less and smaller spheroid colonies in serum-free culture than cells in control groups, suggesting that CD55-Smad4 suppressed the stemness of CRC cells by inhibiting the Wnt/β-catenin pathway. Together, the results of this study provide valuable information for the development of a novel strategy for cancer-targeting gene-virotherapy and provide a deeper understanding of the critical significance of Smad4 in gene therapy of CRC. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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18 pages, 3762 KiB

Open AccessArticle

Fluorescent Tagged Vaccinia Virus Genome Allows Rapid and Efficient Measurement of Oncolytic Potential and Discovery of Oncolytic Modulators

by Franck Gallardo, Doris Schmitt, Renée Brandely, Catherine Brua, Nathalie Silvestre, Annie Findeli, Johann Foloppe, Sokunthea Top, Sandrine Kappler-Gratias, Charlotte Quentin-Froignant, Renaud Morin, Jean-Michel Lagarde, Kerstin Bystricky, Stéphane Bertagnoli and Philippe Erbs

Biomedicines 2020, 8(12), 543; https://doi.org/10.3390/biomedicines8120543 - 26 Nov 2020

Cited by 6 | Viewed by 2765

Abstract

As a live biologic agent, oncolytic vaccinia virus has the ability to target and selectively amplify at tumor sites. We have previously reported that deletion of thymidine kinase and ribonucleotide reductase genes in vaccinia virus can increase the safety and efficacy of the [...] Read more.

As a live biologic agent, oncolytic vaccinia virus has the ability to target and selectively amplify at tumor sites. We have previously reported that deletion of thymidine kinase and ribonucleotide reductase genes in vaccinia virus can increase the safety and efficacy of the virus. Here, to allow direct visualization of the viral genome in living cells, we incorporated the ANCH target sequence and the OR3-Santaka gene in the double-deleted vaccinia virus. Infection of human tumor cells with ANCHOR3-tagged vaccinia virus enables visualization and quantification of viral genome dynamics in living cells. The results show that the ANCHOR technology permits the measurement of the oncolytic potential of the double deleted vaccinia virus. Quantitative analysis of infection kinetics and of viral DNA replication allow rapid and efficient identification of inhibitors and activators of oncolytic activity. Our results highlight the potential application of the ANCHOR technology to track vaccinia virus and virtually any kind of poxvirus in living cells. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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21 pages, 4186 KiB

Open AccessArticle

Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes

by Dmitry V. Chouljenko, Jun Ding, I-Fang Lee, Yanal M. Murad, Xuexian Bu, Guoyu Liu, Zahid Delwar, Yi Sun, Sheng Yu, Ismael Samudio, Ronghua Zhao and William Wei-Guo Jia

Biomedicines 2020, 8(11), 484; https://doi.org/10.3390/biomedicines8110484 - 09 Nov 2020

Cited by 27 | Viewed by 3624

Abstract

Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic [...] Read more.

Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herpes simplex virus type 1 (VG161) that carries genes coding for IL-12, IL-15, and IL-15 receptor alpha subunit, along with a peptide fusion protein capable of disrupting PD-1/PD-L1 interactions. The VG161 virus replicates efficiently and exhibits robust cytotoxicity in multiple tumor cell lines. Moreover, the encoded cytokines and the PD-L1 blocking peptide work cooperatively to boost immune cell function. In vivo testing in syngeneic CT26 and A20 tumor models reveals superior efficacy when compared to a backbone virus that does not express exogenous genes. Intratumoral injection of VG161 induces abscopal responses in non-injected distal tumors and grants resistance to tumor re-challenge. The robust anti-tumor effect of VG161 is associated with T cell and NK cell tumor infiltration, expression of Th1 associated genes in the injection site, and increased frequency of splenic tumor-specific T cells. VG161 also displayed a superb safety profile in GLP acute and repeated injection toxicity studies performed using cynomolgus monkeys. Overall, we demonstrate that VG161 can induce robust oncolysis and stimulate a robust anti-tumor immune response without sacrificing safety. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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22 pages, 8949 KiB

Open AccessArticle

Engineering and Preclinical Evaluation of Western Reserve Oncolytic Vaccinia Virus Expressing A167Y Mutant Herpes Simplex Virus Thymidine Kinase

by S. M. Bakhtiar UL Islam, Young Mi Hong, Mefotse saha Cyrelle Ornella, Daniel Ngabire, Hyunjung Jang, Euna Cho, Eung-Kyun Kim, Jessye Jin Joo Hale, Cy Hyun Kim, Soon Cheol Ahn, Mong Cho and Tae-Ho Hwang

Biomedicines 2020, 8(10), 426; https://doi.org/10.3390/biomedicines8100426 - 16 Oct 2020

Cited by 5 | Viewed by 4044

Abstract

Viral replication of thymidine kinase deleted (tk⁻) vaccinia virus (VV) is attenuated in resting normal cells, enabling cancer selectivity, however, replication potency of VV-tk⁻ appears to be diminished in cancer cells. Previously, we found that wild-type herpes simplex [...] Read more.

Viral replication of thymidine kinase deleted (tk⁻) vaccinia virus (VV) is attenuated in resting normal cells, enabling cancer selectivity, however, replication potency of VV-tk⁻ appears to be diminished in cancer cells. Previously, we found that wild-type herpes simplex virus (HSV)-tk (HSV-tk) disappeared in most of the recombinant VV after multiple screenings, and only a few recombinant VV containing naturally mutated HSV-tk remained stable. In this study, VV-tk of western reserve (WR) VV was replaced by A167Y mutated HSV-tk (HSV-tk_418m), to alter nucleoside selectivity from broad spectrum to purine exclusive selectivity. WOTS-418 remained stable after numerous passages. WOTS-418 replication was significantly attenuated in normal cells, but cytotoxicity was almost similar to that of wild type WR VV in cancer cells. WOTS-418 showed no lethality following a 5 × 10⁸ PFU intranasal injection, contrasting WR VV, which showed 100% lethality at 1 × 10⁵ PFU. Additionally, ganciclovir (GCV) but not BvdU inhibited WOTS-418 replication, confirming specificity to purine nucleoside analogs. The potency of WOTS-418 replication inhibition by GCV was > 10-fold higher than that of our previous truncated HSV-tk recombinant OTS-412. Overall, WOTS-418 demonstrated robust oncolytic efficacy and pharmacological safety which may delegate it as a candidate for future clinical use in OV therapy. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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33 pages, 12115 KiB

Open AccessArticle

Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5

by Rafael Guerrero, Carlos Guerrero and Orlando Acosta

Biomedicines 2020, 8(8), 242; https://doi.org/10.3390/biomedicines8080242 - 24 Jul 2020

Cited by 6 | Viewed by 3193

Abstract

Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface [...] Read more.

Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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Open AccessArticle

Comparison of Liver Detargeting Strategies for Systemic Therapy with Oncolytic Adenovirus Serotype 5

by Tien V. Nguyen, Mary E. Barry, Mallory A. Turner, Catherine M. Crosby, Miguel A. Trujillo, John C. Morris III and Michael A. Barry

Biomedicines 2017, 5(3), 46; https://doi.org/10.3390/biomedicines5030046 - 10 Aug 2017

Cited by 5 | Viewed by 5295

Abstract

Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, [...] Read more.

Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, (3) chemical shielding, or (4) by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5) in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-dl1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-dl1101/07 was next chemically shielded with polyethylene glycol (PEG). While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-dl1101/07, this shielding reduced Ad oncolytic activity. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessArticle

In Vitro Synergistic Enhancement of Newcastle Disease Virus to 5-Fluorouracil Cytotoxicity against Tumor Cells

by Ahmed M. Al-Shammari, Marwa I. Salman, Yahya D. Saihood, Nahi Y. Yaseen, Khansaa Raed, Hiba Kareem Shaker, Aesar Ahmed, Aseel Khalid and Ahlam Duiach

Biomedicines 2016, 4(1), 3; https://doi.org/10.3390/biomedicines4010003 - 29 Jan 2016

Cited by 72 | Viewed by 6368

Abstract

Background: Chemotherapy is one of the antitumor therapies used worldwide in spite of its serious side effects and unsatisfactory results. Many attempts have been made to increase its activity and reduce its toxicity. 5-Fluorouracil (5-FU) is still a widely-used chemotherapeutic agent, especially in [...] Read more.

Background: Chemotherapy is one of the antitumor therapies used worldwide in spite of its serious side effects and unsatisfactory results. Many attempts have been made to increase its activity and reduce its toxicity. 5-Fluorouracil (5-FU) is still a widely-used chemotherapeutic agent, especially in combination with other chemotherapies. Combination therapy seems to be the best option for targeting tumor cells by different mechanisms. Virotherapy is a promising agent for fighting cancer because of its safety and selectivity. Newcastle disease virus is safe, and it selectively targets tumor cells. We previously demonstrated that Newcastle disease virus (NDV) could be used to augment other chemotherapeutic agents and reduce their toxicity by halving the administered dose and replacing the eliminated chemotherapeutic agents with the Newcastle disease virus; the same antitumor activity was maintained. Methods: In the current work, we tested this hypothesis on different tumor cell lines. We used the non-virulent LaSota strain of NDV in combination with 5-FU, and we measured the cytotoxicity effect. We evaluated this combination using Chou–Talalay analysis. Results: NDV was synergistic with 5-FU at low doses when used as a combination therapy on different cancer cells, and there were very mild effects on non-cancer cells. Conclusion: The combination of a virulent, non-pathogenic NDV–LaSota strain with a standard chemotherapeutic agent, 5-FU, has a synergistic effect on different tumor cells in vitro, suggesting this combination could be an important new adjuvant therapy for treating cancer. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Review

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17 pages, 733 KiB

Open AccessReview

Oncolytic Virotherapy for Cancer: Clinical Experience

by Shyambabu Chaurasiya, Yuman Fong and Susanne G. Warner

Biomedicines 2021, 9(4), 419; https://doi.org/10.3390/biomedicines9040419 - 13 Apr 2021

Cited by 40 | Viewed by 6409

Abstract

Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology [...] Read more.

Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology have renewed the interest in using viruses as oncolytic agents. Backed by robust preclinical data, many oncolytic viruses have entered clinical trials. Oncolytic viruses that have completed some levels of clinical trials or are currently undergoing clinical trials are mostly genetically engineered viruses, with the exception of some RNA viruses. Reolysin, an unmodified RNA virus is clinically the most advanced oncolytic RNA virus that has completed different phases of clinical trials. Other oncolytic viruses that have been studied in clinical trials are mostly DNA viruses that belong to one of the three families: herpesviridae, poxviridae or adenoviridae. In this review work we discuss recent clinical studies with oncolytic viruses, especially herpesvirus, poxvirus, adenovirus and reovirus. In summary, the oncolytic viruses tested so far are well tolerated, even in immune-suppressed patients. For most oncolytic viruses, mild and acceptable toxicities are seen at the currently defined highest feasible doses. However, anti-tumor efficacies of oncolytic viruses have been modest, especially when used as monotherapy. Therefore, the potency of oncolytic viruses needs to be enhanced for more oncolytic viruses to hit the clinic. Aiming to achieve higher therapeutic benefits, oncolytic viruses are currently being studied in combination with other therapies. Here we discuss the currently available clinical data on oncolytic viruses, either as monotherapy or in combination with other treatments. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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10 pages, 1164 KiB

Open AccessReview

Design and Engineering of Deimmunized Vaccinia Viral Vectors

by Kevin Song and Mariya Viskovska

Biomedicines 2020, 8(11), 491; https://doi.org/10.3390/biomedicines8110491 - 11 Nov 2020

Cited by 9 | Viewed by 2819

Abstract

Vaccinia viral (VV) vectors are increasingly used in oncolytic virus therapy and vaccine development for cancer and infectious diseases. However, their effectiveness is hindered by the strong anti-viral immune response induced by the viral vector. In this review, we discuss the strategies to [...] Read more.

Vaccinia viral (VV) vectors are increasingly used in oncolytic virus therapy and vaccine development for cancer and infectious diseases. However, their effectiveness is hindered by the strong anti-viral immune response induced by the viral vector. In this review, we discuss the strategies to deimmunize vaccinia viral vector. One approach is to mask the virus from the neutralization antibody responses by mapping and eliminating of B-cell epitopes on the viral membrane proteins. The recombinant VVs contain one or more viral glycoproteins with mutations in the neutralizing antibody epitopes, resulting in viral escape from neutralization. In addition, a regulator of complement activation (e.g., CD55) can be expressed on the surface of the virus particle, leading to increased resistance to complement-mediated neutralization. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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20 pages, 677 KiB

Open AccessReview

Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses

by Anne Everts, Melissa Bergeman, Grant McFadden and Vera Kemp

Biomedicines 2020, 8(11), 474; https://doi.org/10.3390/biomedicines8110474 - 05 Nov 2020

Cited by 24 | Viewed by 4840

Abstract

Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their [...] Read more.

Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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16 pages, 894 KiB

Open AccessEditor’s ChoiceReview

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

by Zong Sheng Guo, Michael T. Lotze, Zhi Zhu, Walter J. Storkus and Xiao-Tong Song

Biomedicines 2020, 8(7), 204; https://doi.org/10.3390/biomedicines8070204 - 10 Jul 2020

Cited by 41 | Viewed by 7465

Abstract

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. [...] Read more.

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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20 pages, 344 KiB

Open AccessEditor’s ChoiceReview

Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis

by Volker Schirrmacher

Biomedicines 2020, 8(3), 61; https://doi.org/10.3390/biomedicines8030061 - 16 Mar 2020

Cited by 39 | Viewed by 4544

Abstract

This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight [...] Read more.

This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight systemic disease, be it micro-metastatic or metastatic. The analysis includes only studies with a proven therapeutic effect. A clear-cut difference is observed with regard to major adverse events (WHO grades 3–4). Such severe side effects are not observed with cancer vaccines/oncolytic viruses while they are seen with all the other systemic therapies. Reasons for this difference are discussed. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

20 pages, 1010 KiB

Open AccessEditor’s ChoiceReview

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

by Volker Schirrmacher

Biomedicines 2020, 8(3), 55; https://doi.org/10.3390/biomedicines8030055 - 06 Mar 2020

Cited by 12 | Viewed by 3819

Abstract

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity [...] Read more.

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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Open AccessReview

Viroimmunotherapy for Colorectal Cancer: Clinical Studies

by Shyambabu Chaurasiya and Susanne Warner

Biomedicines 2017, 5(1), 11; https://doi.org/10.3390/biomedicines5010011 - 10 Mar 2017

Cited by 22 | Viewed by 5425

Abstract

Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an [...] Read more.

Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an enemy to oncolytic viral therapy. Thinking that oncolysis would be the only mechanism for cell death, oncolytic virologists theorized that immune clearance was a detriment to oncolysis. Recent advances in our understanding of the tumor microenvironment, and the interplay of tumor survival and a patient’s immune system have called into question our understanding of both arenas. It remains unclear what combination of restrictions or enhancements of innate and/or cell-mediated immunity can yield the highest likelihood of viral efficacy. This article reviews the variety of mechanisms explored for viruses such as immunotherapy for colorectal cancer. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

The Continued Promise and Many Disappointments of Oncolytic Virotherapy in Gastrointestinal Malignancies

by Daniel H. Ahn and Tanios Bekaii-Saab

Biomedicines 2017, 5(1), 10; https://doi.org/10.3390/biomedicines5010010 - 04 Mar 2017

Cited by 10 | Viewed by 4583

Abstract

Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium [...] Read more.

Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium for cancer therapy. While this approach has garnered much interest over the past several decades, there has not been significant headway across various tumor types. The recent approval of talimogene laherparepvec, a second-generation oncolytic herpes simplex virus type-1, for the treatment of metastatic melanoma, confirms the therapeutic potential of oncolytic viral therapy. Herein, we will highlight and review the role of oncolytic viral therapy in gastrointestinal malignancies while discussing its limitations and potential alternative mechanisms to improve its treatment efficacy. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessReview

Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a “Hammer” and “Anvil”

by Michael Karl Melzer, Arturo Lopez-Martinez and Jennifer Altomonte

Biomedicines 2017, 5(1), 8; https://doi.org/10.3390/biomedicines5010008 - 10 Feb 2017

Cited by 50 | Viewed by 7733

Abstract

Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA [...] Read more.

Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. These strategies include: 1. modification of endogenous virus genes to stimulate interferon induction; 2. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses; 3. vaccination approaches to stimulate adaptive immune responses against a tumor antigen; 4. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. A summary of these approaches will be presented in this review. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessReview

Targeting Autophagy for Oncolytic Immunotherapy

by Lulu Hu, Ke Jiang, Chan Ding and Songshu Meng

Biomedicines 2017, 5(1), 5; https://doi.org/10.3390/biomedicines5010005 - 11 Jan 2017

Cited by 13 | Viewed by 5905

Abstract

Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy [...] Read more.

Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy which can be utilized to design therapeutic combinations using approaches that either induce or block autophagy to potentiate the therapeutic efficacy of OVs. In this article, we review the complicated interplay between autophagy, cancer, immunity, and OV, summarize recent progress in the contribution of OV-perturbed autophagy to oncolytic immunity, and discuss the challenges in targeting autophagy to enhance oncolytic immunotherapy. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

Taking a Stab at Cancer; Oncolytic Virus-Mediated Anti-Cancer Vaccination Strategies

by Amelia Sadie Aitken, Dominic Guy Roy and Marie-Claude Bourgeois-Daigneault

Biomedicines 2017, 5(1), 3; https://doi.org/10.3390/biomedicines5010003 - 04 Jan 2017

Cited by 32 | Viewed by 6863

Abstract

Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer [...] Read more.

Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer therapy. Vaccines targeting cancer antigens can be used to induce anti-tumour immunity and have demonstrated therapeutic efficacy both pre-clinically and clinically. Various approaches now exist and further establish the tremendous potential and adaptability of anti-cancer vaccination. Classical strategies include ex vivo-loaded immune cells, RNA- or DNA-based vaccines and tumour cell lysates. Recent oncolytic virus development has resulted in a surge of novel viruses engineered to induce powerful tumour-specific immune responses. In addition to their use as cancer vaccines, oncolytic viruses have the added benefit of being directly cytolytic to cancer cells and thus promote antigen recognition within a highly immune-stimulating tumour microenvironment. While oncolytic viruses are perfectly equipped for efficient immunization, this complicates their use upon previous exposure. Indeed, the host’s anti-viral counter-attacks often impair multiple-dosing regimens. In this review we will focus on the use of oncolytic viruses for anti-tumour vaccination. We will explore different strategies as well as ways to circumvent some of their limitations. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

Viroimmunotherapy of Thoracic Cancers

by Alexander S. Dash and Manish R. Patel

Biomedicines 2017, 5(1), 2; https://doi.org/10.3390/biomedicines5010002 - 04 Jan 2017

Cited by 6 | Viewed by 5786

Abstract

Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases [...] Read more.

Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases remain as some of the poorest of any cancers. Recent advances in immunotherapy, specifically immune checkpoint inhibitors, have begun to help a small population of patients with advanced lung cancer. People who respond to these immune therapies generally have a durable response and many see dramatic decreases in their disease. However, response to immune therapies remains relatively low. Therefore, intense research is now underway to rationally develop combination therapies to expand the range of patients who will respond to and benefit from immune therapy. One promising approach is with oncolytic viruses. These oncolytic viruses (OVs) have been found to be selective for or have been engineered to preferentially infect and kill cancer cells. In pre-clinical models of different thoracic cancers, it has been found that these viruses can induce immunogenic cell death, increase the number of immune mediators brought into the tumor microenvironment and broaden the neoantigen-specific T cell response. We will review here the literature regarding the application of virotherapy toward augmenting immune responses in thoracic cancers. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts

by Jing Li Huang, Christopher J. LaRocca and Masato Yamamoto

Biomedicines 2016, 4(3), 23; https://doi.org/10.3390/biomedicines4030023 - 19 Sep 2016

Cited by 10 | Viewed by 4524

Abstract

Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and [...] Read more.

Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor), interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies

by Donald Bastin, Scott R. Walsh, Meena Al Saigh and Yonghong Wan

Biomedicines 2016, 4(3), 21; https://doi.org/10.3390/biomedicines4030021 - 24 Aug 2016

Cited by 11 | Viewed by 6290

Abstract

The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being [...] Read more.

The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs) is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization

by Daniel W. Sharp and Edmund C. Lattime

Biomedicines 2016, 4(3), 19; https://doi.org/10.3390/biomedicines4030019 - 12 Aug 2016

Cited by 24 | Viewed by 7178

Abstract

Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by [...] Read more.

Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by encoding and delivering immunostimulatory molecules. This combination makes them an effective platform for the development of immunotherapeutic strategies beyond their primary lytic function. Engineering the viruses to also express tumor-associated antigens (TAAs) allows them to simultaneously serve as therapeutic vaccines, targeting and amplifying an immune response to TAAs. Our group and others have shown that vaccinating intratumorally with a poxvirus that encodes TAAs, in addition to immune stimulatory molecules, can modulate the tumor microenvironment, overcome immune inhibitory pathways, and drive both local and systemic tumor specific immune responses. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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From Benchtop to Bedside: A Review of Oncolytic Virotherapy

by Audrey H. Choi, Michael P. O’Leary, Yuman Fong and Nanhai G. Chen

Biomedicines 2016, 4(3), 18; https://doi.org/10.3390/biomedicines4030018 - 02 Aug 2016

Cited by 50 | Viewed by 7850

Abstract

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not [...] Read more.

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

Fifty Years of Clinical Application of Newcastle Disease Virus: Time to Celebrate!

by Volker Schirrmacher

Biomedicines 2016, 4(3), 16; https://doi.org/10.3390/biomedicines4030016 - 20 Jul 2016

Cited by 62 | Viewed by 7281

Abstract

This review provides an overview of 50 years of basic and clinical research on an oncolytic avian virus, Newcastle Disease Virus (NDV), which has particular anti-neoplastic and immune stimulatory properties. Of special interest is the fact that this biological agent induces immunogenic cell [...] Read more.

This review provides an overview of 50 years of basic and clinical research on an oncolytic avian virus, Newcastle Disease Virus (NDV), which has particular anti-neoplastic and immune stimulatory properties. Of special interest is the fact that this biological agent induces immunogenic cell death and systemic anti-tumor immunity. Furthermore, localized oncolytic virotherapy with NDV was shown to overcome systemic tumor resistance to immune checkpoint blockade immunotherapy. Clinical experience attests to low side effects and a high safety profile. This is due among others to the strong virus-induced type I interferon response. Other viral characteristics are lack of interaction with host cell DNA, lack of genetic recombination and independence of virus replication from cell proliferation. In this millennium, new recombinant strains of viruses are being produced with improved therapeutic properties. Clinical applications include single case observations, case series studies and Phase I to III studies. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Tumor-Associated Macrophages in Oncolytic Virotherapy: Friend or Foe?

by Nicholas L. Denton, Chun-Yu Chen, Thomas R. Scott and Timothy P. Cripe

Biomedicines 2016, 4(3), 13; https://doi.org/10.3390/biomedicines4030013 - 07 Jul 2016

Cited by 36 | Viewed by 7525

Abstract

Cancer therapy remains a challenge due to toxicity limitations of chemotherapy and radiation therapy. Oncolytic viruses that selectively replicate and destroy cancer cells are of increasing interest. In addition to direct cell lysis, these vectors stimulate an anti-tumor immune response. A key regulator [...] Read more.

Cancer therapy remains a challenge due to toxicity limitations of chemotherapy and radiation therapy. Oncolytic viruses that selectively replicate and destroy cancer cells are of increasing interest. In addition to direct cell lysis, these vectors stimulate an anti-tumor immune response. A key regulator of tumor immunity is the tumor-associated macrophage population. Macrophages can either support oncolytic virus therapy through pro-inflammatory stimulation of the anti-tumor response at the cost of hindering direct oncolysis or through immunosuppressive protection of virus replication at the cost of hindering the anti-tumor immune response. Despite similarities in macrophage interaction between adult and pediatric tumors and the abundance of research supporting macrophage modulation in adult tumors, there are few studies investigating macrophage modulation in pediatric cancers or modulation of immunotherapy. We review the current state of knowledge regarding macrophages in cancers and their influence on oncolytic virotherapy. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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