Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses.

Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.

Lay abstract Using viruses in the treatment of cancer goes back to the early 20th century. One of the promising fields in cancer virotherapy is viruses' ability to preferentially lysis tumor cells, either naturally or genetically engineered cells; these viruses are termed 'oncolytic viruses.' As with other therapeutic strategies, resistance to the oncolytic viruses is the main challenge in their application in clinical trials. This review summarizes the mechanisms of resistance to oncolytic viruses and the strategies that have been used to overcome these challenges.

Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation, currently none of these approaches have received approval from the regulatory agencies. CNS tumors, especially glioblastomas, are tumors characterized by highly immunosuppressive tumor microenvironment, limiting the possibility of effectively eliciting an immune response. Moreover, the peculiar anatomic location of these tumors poses relevant challenges in terms of safety, since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension. The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors. Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation. Despite some sporadic complete remissions achieved in clinical trials, the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor. Based on the lessons learned from these unsatisfactory experiences, novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors.

A combination of PD­1/PD­L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review).

Programmed cell death protein­1 (PD­1)/programmed death protein ligand­1 (PD­L1) inhibitors for treatment of a various types of cancers have revolutionized cancer immunotherapy. However, PD­1/PD­L1 inhibitors are associated with a low response rate and are only effective on a small number of patients with cancer. Development of an anti­PD­1/PD­L1 sensitizer for improving response rate and effectiveness of immunotherapy is a challenge. The present study reviews the synergistic effects of PD­1/PD­L1 inhibitor with oncolytic virus, tumor vaccine, molecular targeted drugs, immunotherapy, chemotherapy, radiotherapy, intestinal flora and traditional Chinese medicine, to provide information for development of effective combination therapies.

Pouring petrol on the flames: Using oncolytic virotherapies to enhance tumour immunogenicity.

Oncolytic viruses possess the ability to infect, replicate and lyse malignantly transformed tumour cells. This oncolytic activity amplifies the therapeutic advantage and induces a form of immunogenic cell death, characterized by increased CD8 + T-cell infiltration into the tumour microenvironment. This important feature of oncolytic viruses can result in the warming up of immunologically 'cold' tumour types, presenting the enticing possibility that oncolytic virus treatment combined with immunotherapies may enhance efficacy. In this review, we assess some of the most promising candidates that might be used for oncolytic virotherapy: immunotherapy combinations. We assess their potential as separate agents or as agents combined into a single therapy, where the immunotherapy is encoded within the genome of the oncolytic virus. The development of such advanced agents will require increasingly sophisticated model systems for their preclinical assessment and evaluation. In vivo rodent model systems are fraught with limitations in this regard. Oncolytic viruses replicate selectively within human cells and therefore require human xenografts in immune-deficient mice for their evaluation. However, the use of immune-deficient rodent models hinders the ability to study immune responses against any immunomodulatory transgenes engineered within the viral genome and expressed within the tumour microenvironment. There has therefore been a shift towards the use of more sophisticated ex vivo patient-derived model systems based on organoids and explant co-cultures with immune cells, which may be more predictive of efficacy than contrived and artificial animal models. We review the best of those model systems here.

Evolving Status of Clinical Immunotherapy with Oncolytic Adenovirus.

Cancer immunotherapy targeting immune checkpoint inhibitors shows efficacy in several human cancers, but "cold tumors" that lack immune cells are typically unresponsive. Among the potential therapeutic approaches that could "heat" or promote lymphocyte infiltration of cold tumors, oncolytic viruses have attracted interest for their lytic and immunogenic mechanisms of action. In this article, we review the use of oncolytic adenoviruses in cancer immunotherapy, with a particular focus on preclinical and clinical data of oncolytic adenovirus-triggered immune responses against tumor antigens. We also discuss parameters to consider in clinical trial design and the combination of oncolytic adenoviruses with conventional treatments or other immunotherapies.

Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment.

Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy.

Oncolytic viruses are smart therapeutics against cancer due to their potential to replicate and produce the needed therapeutic dose in the tumor, and to their ability to self-exhaust upon tumor clearance. Oncolytic virotherapy strategies based on the herpes simplex virus are reaching their thirties, and a wide variety of approaches has been envisioned and tested in many different models, and on a range of tumor targets. This huge effort has culminated in the primacy of an oncolytic HSV (oHSV) being the first oncolytic virus to be approved by the FDA and EMA for clinical use, for the treatment of advanced melanoma. The path has just been opened; many more cancer types with poor prognosis await effective and innovative therapies, and oHSVs could provide a promising solution, especially as combination therapies and immunovirotherapies. In this review, we analyze the most recent advances in this field, and try to envision the future ahead of oHSVs.

[Progress in engineering application of human adenovirus].

Human adenoviruses are widespread causative agent that induces respiratory diseases, epidemic keratoconjunctivitis and other related diseases. Adenoviruses are commonly used in experimental and clinical areas. It is one of the most commonly used virus vectors in gene therapy, and it has attracted a lot of attention and has a high research potential in tumor gene therapy and virus oncolytic. Here, we summarize the biological characteristics, epidemiology and current application of adenovirus, in order to provide reference for engineering application of adenovirus.

An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions.

Talimogene laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (OncovexGM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.

A tool with many applications: vesicular stomatitis virus in research and medicine.

INTRODUCTION: Vesicular stomatitis virus (VSV) has long been a useful research tool in virology and recently become an essential part of medicinal products. Vesiculovirus research is growing quickly following its adaptation to clinical gene and cell therapy and oncolytic virotherapy. AREAS COVERED: This article reviews the versatility of VSV as a research tool and biological reagent, its use as a viral and vaccine vector delivering therapeutic and immunogenic transgenes and an oncolytic virus aiding cancer treatment. Challenges such as the immune response against such advanced therapeutic medicinal products and manufacturing constraints are also discussed. EXPERT OPINION: The field of in vivo gene and cell therapy is advancing rapidly with VSV used in many ways. Comparison of VSV's use as a versatile therapeutic reagent unveils further prospects and problems for each application. Overcoming immunological challenges to aid repeated administration of viral vectors and minimizing harmful host-vector interactions remains one of the major challenges. In the future, exploitation of reverse genetic tools may assist the creation of recombinant viral variants that have improved onco-selectivity and more efficient vaccine vector activity. This will add to the preferential features of VSV as an excellent advanced therapy medicinal product (ATMP) platform.

Oncolytic viruses for cancer immunotherapy.

In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains.As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors.Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.

Adenovirus-mediated specific tumor tagging facilitates CAR-T therapy against antigen-mismatched solid tumors.

Chimeric antigen receptor T (CAR-T) therapy faces at least two major obstacles in solid tumors, including to find specific antigen among the heterogeneous tumor mass and to overcome the inhibitory microenvironment. Developing novel strategies to overcome these difficulties has been the burning issue in immunotherapy. Here we came up with the concept of tagging cancer cells by tumor-targeting adenoviruses (Ad). We constructed recombinant Ads expressing CD19 tag driven by tumor-specific promoters, which could label antigenically different tumors for single anti-CD19 CAR-T recognition. One Ad, namely AdC68-TMC-tCD19 could mediate universal tag expression and functional immunological synapse formation between CAR-T and cancer cells. In premixed mice model, all tagged mice survived after CAR-T infusion and tumor volume were inhibited by 91.78%. Furthermore, we combined the tumor tagging ability with oncolysis and generated the replicative AdC68-Sur-E1A-TMC-tCD19. Oncolytic tagging system could diminish established tumors in vivo and prolong mice survival significantly. Therefore, we suggest the universal oncolytic Ad-tagging system in combination with single target CAR-T cells could be a powerful complement in immunotherapy against antigenically mismatched solid tumors.

Immunotherapeutic Potential of TGF-ß Inhibition and Oncolytic Viruses.

In cancer immunotherapy, a patient's own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-ß (TGF-ß)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-ß signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade.

Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies.

Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.

Immunotherapy for hepatocellular carcinoma: Current and future.

Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.

Recent advances in oncolytic virus-based cancer therapy.

Administration of oncolytic viruses (OVs) is an emerging anticancer strategy that exploits the lytic nature of viral replication to enhance the killing of malignant cells. OVs can be used as tools to directly induce cancer cell death and to trigger local and/or systemic immune responses to metastatic cancer in vivo. The effectiveness of OV therapy was initially highlighted by the clinical use of the genetically modified herpes virus, talimogene laherparepvec, for melanoma therapy. A number of OVs are now being evaluated as potential treatments for cancer in clinical trials. In spite of being engineered to specifically target tumor cells, the safety and off-target effects of OV therapy are a concern. The potential safety concerns of OVs are highlighted by current clinical trial criteria, which exclude individuals harbouring other viral infections and people who are immunocompromised. Despite the potential for adverse effects, clinical trials to date revealed relatively minimal adverse immune-related effects, such as fever. With advances in our understanding of virus replication cycles, several novel OVs have emerged. Reverse genetic systems have facilitated the insertion of anticancer genes into a range of OVs to further enhance their tumor-killing capacity. In this review, we highlight the recent advances in OV therapy for a range of human cancers in in vitro and in in vivo animal studies. We further discuss the future of OVs as a therapeutic strategy for a range of life-threatening cancers.

H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future.

The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers anticancer immune responses. The safety and tolerability of H-1PV treatment has been demonstrated in early clinical studies in glioma and pancreatic carcinoma patients. Virus treatment was associated with surrogate signs of efficacy including immune conversion of tumor microenvironment, effective virus distribution into the tumor bed even after systemic administration, and improved patient overall survival compared with historical control. However, monotherapeutic use of the virus was unable to eradicate tumors. Thus, further studies are needed to improve H-1PV's anticancer profile. In this review, we describe H-1PV's anticancer properties and discuss recent efforts to improve the efficacy of H-1PV and, thereby, the clinical outcome of H-1PV-based therapies.

Advances in the techniques and methodologies of cancer gene therapy.

Cancer is the second leading cause of mortality worldwide after cardiovascular diseases, predominantly due to the lack of early symptoms and early diagnosis, and high relapse rate after radical surgery and conventional therapies. Therefore, novel approaches such as gene therapy have raised hope to significantly improve the survival rate of patients with cancers. This review aims to provide up-to-date information concerning gene therapy including improved vectors, suicide genes, cancer suppressor genes, anti-tumor angiogenesis, gene silencing, oncolytic virotherapy, and gene-editing technology. Although specific issues still exist before gene therapy can completely cure cancers, here we highlight the potential of gene therapy in cancer treatment and expect to see continuous breakthroughs in techniques and methodologies of gene therapy.

Therapeutic potency of oncolytic virotherapy-induced cancer stem cells targeting in brain tumors, current status, and perspectives.

Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease.