Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.

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Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Cells ◽

10.3390/cells9020400 ◽

2020 ◽

Vol 9 (2) ◽

pp. 400 ◽

Cited By ~ 12

Author(s):

Hong-My Nguyen ◽

Kirsten Guz-Montgomery ◽

Dipongkor Saha

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Tumor Immunity ◽

Therapeutic Potential ◽

Human Subjects ◽

Genetically Engineered ◽

Oncolytic Viruses ◽

Interleukin 12 ◽

T Helper 1 ◽

Simplex Virus

Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

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Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Cancers ◽

10.3390/cancers11101532 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1532 ◽

Cited By ~ 8

Author(s):

Malfitano ◽

Somma ◽

Prevete ◽

Portella

Keyword(s):

Thyroid Carcinoma ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Differentiated Thyroid Carcinoma ◽

Anaplastic Thyroid Carcinoma ◽

Oncolytic Viruses ◽

Cancer Models ◽

Poorly Differentiated ◽

Immunosuppressive Microenvironment

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed.

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Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets

Current Drug Targets ◽

10.2174/1389450123666220111114649 ◽

2022 ◽

Vol 23 ◽

Author(s):

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Immune System ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Drug Targets ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Cancer Drug ◽

Cancer Therapies ◽

Cellular Expression ◽

Hypoxic Tumor

Abstract: Cancer is now also reflected as a disease of the tumor microenvironment, primarily supposed to be a decontrolled genetic and cellular expression disease. Over the past two decades, significant and rapid progress has been made in recognizing the dynamics of the tumor's microenvironment and its contribution to influencing the response to various anti-cancer therapies and drugs. Modulations in the tumor microenvironment and immune checkpoint blockade are interesting in cancer immunotherapy and drug targets. Simultaneously, the immunotherapeutic strategy can be done by modulating the immune regulatory pathway; however, the tumor microenvironment plays an essential role in suppressing the antitumor's immunity by its substantial heterogeneity. Hypoxia inducible factor (HIF) is a significant contributor to solid tumor heterogeneity and a key stressor in the tumor microenvironment to drive adaptations to prevent immune surveillance. Checkpoint inhibitors here halt the ability of cancer cells to stop the immune system from activating, and in turn, amplify your body's immune system to help destroy cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways and important drugs involved are Ipilimumab and Nivolumab, mainly along with other drugs in this group. Targeting the hypoxic tumor microenvironment may provide a novel immunotherapy strategy, break down traditional cancer therapy resistance, and build the framework for personalized precision medicine and cancer drug targets. We hope that this knowledge can provide insight into the therapeutic potential of targeting Hypoxia and help to develop novel combination approaches of cancer drugs to increase the effectiveness of existing cancer therapies, including immunotherapy.

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Characterization of herpes simplex virus 1 strains as platforms for the development of oncolytic viruses against liver cancer

Liver International ◽

10.1111/j.1478-3231.2011.02628.x ◽

2011 ◽

Vol 31 (10) ◽

pp. 1542-1553 ◽

Cited By ~ 8

Author(s):

Rafaela Argnani ◽

Peggy Marconi ◽

Ilaria Volpi ◽

Elixabet Bolanos ◽

Elvira Carro ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Liver Cancer ◽

Oncolytic Viruses ◽

Herpes Simplex Virus 1 ◽

Simplex Virus

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Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

10.1101/522607 ◽

2019 ◽

Author(s):

Huy-Dung Hoang ◽

Tyson E. Graber ◽

Jian-Jun Jia ◽

Nasana Vaidya ◽

Victoria Gilchrist ◽

...

Keyword(s):

Innate Immunity ◽

Cancer Cells ◽

Translational Control ◽

Mrna Translation ◽

Open Reading Frames ◽

Oncolytic Viruses ◽

Herpes Simplex Virus 1 ◽

Virus Attachment ◽

Cellular Antiviral Response ◽

Simplex Virus

ABSTRACTResidual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain ill-defined. We characterized the translatome of resistant murine “4T1” breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally de-repressed mRNAs involved in ciliary homeostasis including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. Translationally repressed in the uninfected condition, viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5’ leader and is consequently efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5’ leader expression and assign ciliary proteins such as INPP5E to the cellular antiviral response.

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From Conventional Therapies to Immunotherapy: Melanoma Treatment in Review

Cancers ◽

10.3390/cancers12103057 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3057

Author(s):

Lukasz Kuryk ◽

Laura Bertinato ◽

Monika Staniszewska ◽

Katarzyna Pancer ◽

Magdalena Wieczorek ◽

...

Keyword(s):

Cancer Research ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Cancer Therapies ◽

Combination Strategies ◽

Limited Efficacy ◽

Anti Cancer ◽

Melanoma Treatment ◽

Tumor Clearance ◽

Complete Tumor

In this review, we discuss the use of oncolytic viruses and checkpoint inhibitors in cancer immunotherapy in melanoma, with a particular focus on combinatory therapies. Oncolytic viruses are promising and novel anti-cancer agents, currently under investigation in many clinical trials both as monotherapy and in combination with other therapeutics. They have shown the ability to exhibit synergistic anticancer activity with checkpoint inhibitors, chemotherapy, radiotherapy. A coupling between oncolytic viruses and checkpoint inhibitors is a well-accepted strategy for future cancer therapies. However, eradicating advanced cancers and tailoring the immune response for complete tumor clearance is an ongoing problem. Despite current advances in cancer research, monotherapy has shown limited efficacy against solid tumors. Therefore, current improvements in virus targeting, genetic modification, enhanced immunogenicity, improved oncolytic properties and combination strategies have a potential to widen the applications of immuno-oncology (IO) in cancer treatment. Here, we summarize the strategy of combinatory therapy with an oncolytic vector to combat melanoma and highlight the need to optimize current practices and improve clinical outcomes.

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HSV-1 Oncolytic Viruses from Bench to Bedside: An Overview of Current Clinical Trials

Cancers ◽

10.3390/cancers12123514 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3514

Author(s):

Marilin Koch ◽

Sean Lawler ◽

E. Chiocca

Keyword(s):

Clinical Trials ◽

Oncolytic Viruses ◽

Talimogene Laherparepvec ◽

Herpes Simplex Virus 1 ◽

Therapy Options ◽

Fda Approval ◽

Tumor Selectivity ◽

Simplex Virus ◽

Oncologic Therapy ◽

Hsv 1

Herpes simplex virus 1 (HSV-1) provides a genetic chassis for several oncolytic viruses (OVs) currently in clinical trials. Oncolytic HSV1 (oHSV) have been engineered to reduce neurovirulence and enhance anti-tumor lytic activity and immunogenicity to make them attractive candidates in a range of oncology indications. Successful clinical data resulted in the FDA-approval of the oHSV talimogene laherparepvec (T-Vec) in 2015, and several other variants are currently undergoing clinical assessment and may expand the landscape of future oncologic therapy options. This review offers a detailed overview of the latest results from clinical trials as well as an outlook on newly developed HSV-1 oncolytic variants with improved tumor selectivity, replication, and immunostimulatory capacity and related clinical studies.

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Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms21207449 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7449

Author(s):

Jana de Sostoa ◽

Valérie Dutoit ◽

Denis Migliorini

Keyword(s):

Brain Tumors ◽

Therapeutic Potential ◽

Synergistic Effects ◽

Clinical Results ◽

Oncolytic Viruses ◽

Cancer Therapies ◽

Malignant Brain Tumors ◽

Immunosuppressive Microenvironment ◽

Novel Therapeutic Strategies ◽

Preclinical And Clinical Studies

Malignant brain tumors remain incurable diseases. Although much effort has been devoted to improving patient outcome, multiple factors such as the high tumor heterogeneity, the strong tumor-induced immunosuppressive microenvironment, and the low mutational burden make the treatment of these tumors especially challenging. Thus, novel therapeutic strategies are urgent. Oncolytic viruses (OVs) are biotherapeutics that have been selected or engineered to infect and selectively kill cancer cells. Increasingly, preclinical and clinical studies demonstrate the ability of OVs to recruit T cells and induce durable immune responses against both virus and tumor, transforming a “cold” tumor microenvironment into a “hot” environment. Besides promising clinical results as a monotherapy, OVs can be powerfully combined with other cancer therapies, helping to overcome critical barriers through the creation of synergistic effects in the fight against brain cancer. Although many questions remain to be answered to fully exploit the therapeutic potential of OVs, oncolytic virotherapy will clearly be part of future treatments for patients with malignant brain tumors.

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Attenuated multi–mutated herpes simplex virus–1 for the treatment of malignant gliomas

Nature Medicine ◽

10.1038/nm0995-938 ◽

1995 ◽

Vol 1 (9) ◽

pp. 938-943 ◽

Cited By ~ 526

Author(s):

Toshihiro Mineta ◽

Samuel D. Rabkin ◽

Takahito Yazaki ◽

William D. Hunter ◽

Robert L. Martuza

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Malignant Gliomas ◽

Herpes Simplex Virus 1 ◽

Simplex Virus

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Arenavirus Therapy in Combination with Checkpoint Blockade as an Effective Way for Better Tumour Clearance

Cellular Physiology and Biochemistry ◽

10.33594/000000472 ◽

2021 ◽

pp. 726-738

Keyword(s):

Immune Activation ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Tumor Treatment ◽

Recombinant Viruses ◽

Broad Variety ◽

Cancer Types ◽

Simplex Virus ◽

Tumor Types

Viruses have been widely used to treat cancer for many years and they achieved tremendous success in clinical trials with outstanding results, which has led to the foundation of companies that develop recombinant viruses for a better tumor treatment. Even though there has been a great progress in the field of viral tumor immunotherapy, until now only one virus, the oncolytic virus talimogene laherparepvec (TVEC), a genetically modified herpes simplex virus type 1 (T-VEC), has been approved by the FDA for cancer treatment. Although oncolytic viruses showed progress in certain cancer types and patient populations but they have yet shown limited efficacy when it comes to solid tumors. Only recently it was demonstrated that the immune stimulatory aspect of oncolytic viruses can strongly contribute to their anti-tumoral activity. One specific example in this context are arenaviruses, which have been shown to be non-cytopathic in nature lead to the massive immune activation within the tumor resulting in strong anti-tumoral activity. This strong immune activation might be also linked to their noncytopathic features, as their immune stimulatory potential is not self-limiting as is the case for oncolytic viruses due to their fast eradication by anti-viral immune effects. Because of this strong immune activation, arenaviruses appear superior to oncolytic viruses when it comes to potent and long-lasting anti-tumor effects in a broad variety of tumor types. Currently one of the most promising therapeutics which has turned to be very much beneficial for the treatment of different cancer types is represented by antibodies targeting checkpoint inhibitors such as PD-1/PD-L-1. In this review, we will summarize anti-tumoral effects of arenaviruses, and will discuss their potential to be combined with checkpoint inhibitors for a more efficient tumor treatment, which further emphasizes that arenavirus therapy as a viroimmunotherapy can be an efficient tool for the better clearance of tumors.

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