Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.

• Hepatocellular carcinoma
• Immunotherapy
• Liver transplantation
• Neoadjuvant and adjuvant immunotherapy
• Immune checkpoint inhibitors
• Vaccine therapies
• Oncolytic viruses
• Adoptive cell therapy
• Antigen-targeting antibodies
• Diagnostic biomarkers

• antitumor immunity
• challenges
• combination therapy
• immune checkpoint inhibitor
• oncolytic viruses (OVs)

• Humans
• Oncolytic Virotherapy
• Oncolytic Viruses
• Neoplasms
• Immunotherapy
• Tumor Microenvironment

• Ras pathway
• chemotherapy
• oncolytic viral therapy
• oncolytic virus
• reovirus

• B34 the Canadian Breast Cancer Foundation
• RT757538 the Cancer Research Society
• MOP-82850 Canadian Institutes of Health Research (RNJ)

• 16712019 MEXT | Japan Society for the Promotion of Science (JSPS)
• 09028017 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
• JP15cm0106015 Japan Agency for Medical Research and Development (AMED)

Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and is prone to intra- and extrahepatic metastasis due to the anatomical and functional characteristics of the liver. Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation, immune checkpoint inhibitors (ICIs) are increasingly being used to treat HCC. Several immunotherapeutic agents, along with their combinations, have been clinically approved to treat advanced or recurrent HCC. This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1–3 trials as monotherapy or combination therapy. Furthermore, we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines. Combination therapy is a promising potential treatment option. These immunotherapies are also summarized in this review, which provides insights into the advantages, limitations, and novel angles for future research in establishing viable and alternative therapies against HCC.

• Recurrent hepatocellular carcinoma
• Immunotherapy
• Immune checkpoint inhibitor
• Chimeric antigen receptor-engineered T cell
• Oncolytic virus
• Tumor vaccine

• DOTAP
• coxsackievirus and adenovirus receptor
• folate targeting
• liposome
• oncolytic virus

• Hepatocellular Carcinoma
• Hepatocellular Carcinoma management
• Hepatocellular Carcinoma therapy
• Immunotherapy
• Molecular targeted therapy

Cancer cells are distinguished by enhanced glucose uptake and an aerobic glycolysis pathway in which its products support metabolic demands for cancer cell growth and proliferation. Inhibition of aerobic glycolysis is a smart therapeutic approach to target the progression of the cancer cell. We employed acarbose (ACA), a particular alpha-glucosidase inhibitor, to induce glucose deprivation combined with oncolytic Newcastle disease virus (NDV) to enhance antitumor activity. In this work, we used a mouse model of breast cancer with mammary adenocarcinoma tumor cells (AN3) that were treated with ACA, NDV, and a combination of both. The study included antitumor efficacy, relative body weight, glucose level, hexokinase (HK-1) level by ELISA, glycolysis product (pyruvate), total ATP, oxidative stress (ROS and reduced glutathione), and apoptosis by immunohistochemistry. The results showed significant antitumor efficacy against breast cancer after treatment with combination therapy. Antitumor efficacy was accompanied by a reduction in body weight and glucose level, HK-1 downregulation, inhibition of glycolysis products (pyruvate), total ATP, induction of oxidative stress (increase ROS and decrease reduced glutathione), and apoptotic cell death. The findings propose a novel anti–breast cancer combination involving the suppression of glycolysis, glucose deprivation, oxidative stress, and apoptosis, which can be translated clinically.

• Apoptosis
• Breast cancer
• Live-attenuated poliovirus
• Oncolytic virotherapy

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.

• Non-BCR-ABL targeted drugs
• antioxidants
• chronic myeloid leukemia
• exosomes
• marine organisms
• oncolytic therapy
• quiescent leukemia stem cells
• tyrosine kinase inhibitors

Malignant mesothelioma (MM) is an aggressive asbestos-related cancer, against which no curative modalities exist. Oncolytic virotherapy is a promising therapeutic approach, for which MM is an ideal candidate; indeed, the pleural location provides direct access for the intra-tumoral injection of oncolytic viruses (OVs). Some non-human OVs offer advantages over human OVs, including the non-pathogenicity in humans and the absence of pre-existing immunity. We previously showed that caprine herpesvirus 1 (CpHV-1), a non-pathogenic virus for humans, can kill different human cancer cell lines. Here, we assessed CpHV-1 effects on MM (NCI-H28, MSTO, NCI-H2052) and non-tumor mesothelial (MET-5A) cells. We found that CpHV-1 reduced cell viability and clonogenic potential in all MM cell lines without affecting non-tumor cells, in which, indeed, we did not detect intracellular viral DNA after treatment. In particular, CpHV-1 induced MM cell apoptosis and accumulation in G0/G1 or S cell cycle phases. Moreover, CpHV-1 strongly synergized with cisplatin, the drug currently used in MM chemotherapy, and this agent combination did not affect normal mesothelial cells. Although further studies are required to elucidate the mechanisms underlying the selective CpHV-1 action on MM cells, our data suggest that the CpHV-1-cisplatin combination could be a feasible strategy against MM.

• apoptosis
• caprine herpesvirus 1 (CpHV-1)
• cisplatin
• malignant mesothelioma (MM)
• oncolytic virus (OV)
• synergism

• cancer immune therapy
• cancer therapy
• combination therapy
• immunotherapy
• oncolytic virus
• small molecule

• n.a. Christian Doppler Forschungsgesellschaft

• dynamics
• fluorescence imaging
• molecular imaging
• oncolytic virotherapy
• replicating viruses

Oncolytic virus therapy has emerged as a promising treatment option against cancer. To date, oncolytic viruses have been developed for malignant tumors, but the need for this new therapeutic modality also exists for benign and slow‐growing tumors. G47∆ is an oncolytic herpes simplex virus type 1 (HSV‐1) with an enhanced replication capability highly selective to tumor cells due to genetically engineered, triple mutations in the γ34.5, ICP6 and α47 genes. To create a powerful, but safe oncolytic HSV‐1 that replicates efficiently in tumors regardless of growth speed, we used a bacterial artificial chromosome system that allows a desired promoter to regulate the expression of the ICP6 gene in the G47∆ backbone. Restoration of the ICP6 function in a tumor‐specific manner using the hTERT promoter led to a highly capable oncolytic HSV‐1. T‐hTERT was more efficacious in the slow‐growing OS‐RC‐2 and DU145 tumors than the control viruses, while retaining a high efficacy in the fast‐growing U87MG tumors. The safety features are also retained, as T‐hTERT proved safe when inoculated into the brain of HSV‐1 sensitive A/J mice. This new technology should facilitate the use of oncolytic HSV‐1 for all tumors irrespective of growth speed.

• G47∆
• ICP6
• hTERT
• herpes simplex virus type 1
• oncolytic virus

In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research.

A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software.

In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters.

The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.

• Bibliometric
• Cancer
• Dynamic co-citation
• Oncolytic virus
• Virotherapy

• G protein less (GLESS)–fusion-associated small transmembrane (FAST)–vesicular stomatitis virus (VSV)
• glioma
• neurotoxicity

• drug development
• targeted therapies
• drug safety

• Animals
• Dogs/blood
• Dogs/immunology
• Dogs/virology
• Male
• Body Temperature
• Body Weight
• DNA, Viral/blood
• Immunity/immunology
• Injections, Intravenous
• Leukocyte Count
• Oncolytic Virotherapy/adverse effects
• Oncolytic Viruses/physiology
• Organ Specificity
• Tissue Distribution
• Vaccinia virus/physiology
• Virus Shedding/physiology

As a promising therapeutic strategy, oncolytic virotherapy has shown potent anticancer efficacy in numerous pre-clinical and clinical trials. Oncolytic viruses have the capacity for conditional-replication within carcinoma cells leading to cell death via multiple mechanisms, including direct lysis of neoplasms, induction of immunogenic cell death, and elicitation of innate and adaptive immunity. In addition, these viruses can be engineered to express cytokines or chemokines to alter tumor microenvironments. Combination of oncolytic virotherapy with other antitumor therapeutic modalities, such as chemotherapy and radiation therapy as well as cancer immunotherapy can be used to target a wider range of tumors and promote therapeutic efficacy. In this review, we outline the basic biological characteristics of oncolytic viruses and the underlying mechanisms that support their use as promising antitumor drugs. We also describe the enhanced efficacy attributed to virotherapy combined with other drugs for the treatment of cancer.

• Antitumor
• Combination therapy
• Immunogenic cell death
• Innate and adaptive immunity
• Oncolysis
• Oncolytic virus
• Tumor tropism

• Glioblastoma multiforme
• delivery systems
• drug targets
• epidemiology
• pathogenesis
• therapies

• adoptive cellular immunotherapy
• cancer vaccines
• hepatocellular carcinoma
• immune checkpoint inhibitors
• immunotherapy
• microsatellite instability
• oncolytic viruses
• tumor microenvironment

• Anticancer therapy
• Cytotoxicity
• Hexokinase inhibitor
• Pyruvate
• Warburg effect

Colorectal cancer is an aggressive malignancy for which there are limited treatment options. Oncolytic vaccinia virus is being developed as a novel strategy for cancer therapy. Arming vaccinia virus with immunostimulatory cytokines can enhance the tumor cell-specific replication and antitumor efficacy. Interleukin-24 (IL-24) is an important immune mediator, as well as a broad-spectrum tumor suppressor. We constructed a targeted vaccinia virus of Guang9 strain harboring IL-24 (VG9-IL-24) to evaluate its antitumor effects. In vitro, VG9-IL-24 induced an increased number of apoptotic cells and blocked colorectal cancer cells in the G₂/M phase of the cell cycle. VG9-IL-24 induced apoptosis in colorectal cancer cells via multiple apoptotic signaling pathways. In vivo, VG9-IL-24 significantly inhibited the tumor growth and prolonged the survival both in human and murine colorectal cancer models. In addition, VG9-IL-24 stimulated multiple antitumor immune responses and direct bystander antitumor activity. Our results indicate that VG9-IL-24 can inhibit the growth of colorectal cancer tumor by inducing oncolysis and apoptosis as well as stimulating the antitumor immune effects. These findings indicate that VG9-IL-24 may exert a potential therapeutic strategy for combating colorectal cancer.

Targeted oncolytic vaccinia virus is an attractive candidate for cancer therapy due to its replication causing lysis of infected tumor cells as well as a delivery vector to overexpress therapeutic transgenes. This study constructed a novel oncolytic vaccinia virus carrying granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-24 (IL-24) double genes to improve efficacy for cancer therapy.

Vaccinia virus co-expressing GM-CSF and IL-24 based on Chinese Guang9 strain (VG9-GMCSF-IL24) was constructed with disruption of the viral thymidine kinase (TK) gene. The cytotoxicity of VG9-GMCSF-IL24 in various cell lines was assessed by MTT. The synergistic antitumor effect of VG9-GMCSF-IL24 in vivo was assessed on multiple tumor models.

In vitro cytotoxicity assay showed that VG9-GMCSF-IL24 exerted a strongly cytotoxic effect on cancer cells, but with no significant cytotoxicity to normal cells. Significant tumor growth inhibition and prolonged survival were observed in different tumor models treated with VG9-GMCSF-IL24. Additionally, systemic and specific antitumoral immunity was investigated in vivo, and enhanced antitumor immunity was observed in VG9-GMCSF-IL24-treated mice.

Our results indicated that VG9-mediated GM-CSF and IL-24 co-expression performed cooperative and overlapping antitumor effect. As a novel and effective therapeutic strategy for cancer, the combination of oncolysis and immunotherapy with vaccinia virus carrying one or more immunostimulatory genes may have a satisfactory clinical application prospect.

• GM-CSF
• IL-24
• cancer therapy
• immunotherfapy
• oncolytic vaccinia virus

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

• E. coli nitroreductase gene
• brain tumor
• gene therapy
• prodrug activator
• retroviral replicating vector

• Animals
• Aziridines/pharmacology
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Brain Neoplasms/therapy
• Cell Line, Tumor
• Cytosine Deaminase/biosynthesis
• Cytosine Deaminase/genetics
• Escherichia coli Proteins/biosynthesis
• Escherichia coli Proteins/genetics
• Flucytosine/pharmacology
• Genetic Therapy
• Genetic Vectors
• Glioma/genetics
• Glioma/metabolism
• Glioma/pathology
• Glioma/therapy
• Leukemia Virus, Gibbon Ape
• Neoplasms, Experimental/genetics
• Neoplasms, Experimental/metabolism
• Neoplasms, Experimental/pathology
• Neoplasms, Experimental/therapy
• Nitroreductases/biosynthesis
• Nitroreductases/genetics
• Prodrugs/pharmacology
• Rats, Inbred F344
• Saccharomyces cerevisiae Proteins/biosynthesis
• Saccharomyces cerevisiae Proteins/genetics

Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.

• GFP
• autophagy
• hTERT
• oncolytic adenovirus
• p53

• Bone repair
• Controlled release and expression
• Electrical stimulation
• Electroactive composite scaffold
• Human bone morphogenetic protein-4

Targeting cancer cells metabolism is promising strategy in inhibiting cancer cells progression that are known to exhibit increased aerobic glycolysis. We used the glucose analog 2-Deoxyglucose (2-DG) as a competitor molecule of glucose. To further enhance the effectiveness of 2-DG, the Newcastle disease virus (NDV) was used as a combination virotherapy to enhance the anti-tumor effect. Human and mouse-breast cancer cells were treated by NDV and/or 2-DG. The effect was analyzed by study cell viability, apoptosis and level of glyceraldehyde3-phosphate (GAPDH) by ELISA and QPCR assays. Synergistic cytotoxicity was found after a 72-h treatment of human- and mouse-breast cancer cells with 2-DG in combination with NDV at different concentrations. The synergistic cytotoxicity was accompanied by apoptotic cell death and GAPDH downregulation and inhibition to glycolysis product pyruvate. The combination treatment showed significant tumor growth inhibition compared to single treatments in vivo. Our results suggest the effectiveness of a novel strategy for anti-breast cancer therapy through glycolysis inhibition and GAPDH downregulation.

• Warburg effect
• breast cancer model
• cancer metabolism
• glycolysis inhibition
• virotherapy

• Oncolytic virus
• antitumor immune response
• herpes simplex virus
• immunotherapy
• newcastle disease virus
• oncolysis
• productive infection
• reovirus
• vaccinia virus
• vesicular stomatitis virus

• Cancer
• Genetically engineered
• Immune escape
• Oncolytic herpes simplex virus
• Oncolytic viral therapy

• Cancer vaccines
• Gene therapy
• Oncolytic vector
• Oncolytic viruses
• Vaccinia virus

• Animals
• CRISPR-Cas Systems
• Cancer Vaccines/genetics
• Cancer Vaccines/immunology
• Gene Targeting
• Genetic Therapy/methods
• Genetic Vectors/genetics
• Humans
• Immunotherapy
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/therapy
• Oncolytic Virotherapy/methods
• Oncolytic Viruses/genetics
• Vaccinia virus/genetics

• chimeric virus
• fusion protein
• hepatocellular carcinoma
• immunotherapy
• oncolytic virus
• syncytia

Temozolomide (TMZ) is widely used to treat melanoma; however, response rates to TMZ are low because of rapid and frequent resistance. Conditionally, replicative adenoviruses (CRAds) are an effective and promising approach. The receptor for adenovirus is coxsackie‐adenovirus receptor (CAR), which is poorly expressed in most cells. However, CD46, which is the receptor of species B adenoviruses (Ads), is highly expressed in many cells.

We constructed CRAd F5/35‐ZD55‐IL‐24, which uses the viral receptors CAR and CD46 for entry into cells. We investigated the antitumor effect of F5/35‐ZD55‐IL‐24 in combination with TMZ to treat melanoma in vitro and in vivo.

The \results indicated that F5/35‐ZD55‐IL‐24 in combination with TMZ produced additive or synergistic antitumor and pro‐apoptotic effects in melanoma cells. The combination of F5/35‐ZD55‐IL‐24 and TMZ significantly inhibited the growth of melanoma in vivo. In addition, the antitumor effect of F5/35‐ZD55‐IL‐24 was superior to that of ZD55‐IL‐24 and ZD55‐IL‐24 combined with TMZ.

The use of F5/35‐ZD55‐IL‐24 in conjunction with TMZ is a promising approach for anti‐melanoma therapy.

Our results indicated that F5/35‐ZD55‐IL‐24 in combination with TMZ produced additive or synergistic antitumor effect and pro‐apoptotic effect in melanoma cells highly expressed CD46. The combination of F5/35‐ZD55‐IL‐24 and TMZ significantly inhibited the growth of melanoma in vivo. We also found the antitumor effect of F5/35‐ZD55‐IL‐24 was superior to ZD55‐IL‐24, the combination of F5/35‐ZD55‐IL‐24 and TMZ had a more significant antitumor effect than ZD55‐IL‐24 combining with TMZ.

• CRAd
• F5/35
• conditionally replicative adenovirus
• interleukin 24
• melanoma
• temozolomide

• ING4
• acute myeloid leukemia
• combination therapy
• cytarabine
• oncolytic vaccinia virus

• hepatocellular carcinoma
• liver cirrhosis
• oncolytic virus
• transhepatic angiography

Oncolytic viruses are lytic for many types of cancers but are attenuated or replication-defective in normal tissues. Aside from tumor lysis, oncolytic viruses can induce host immune responses against cancer cells and may thus be viewed as a form of immunotherapy. Although recent successes with checkpoint inhibitors have shown that enhancing antitumor immunity can be effective, the dynamic nature of the immunosuppressive tumor microenvironment presents significant hurdles to the broader application of these therapies. Targeting one immune-suppressive pathway may not be sufficient to eliminate tumors. Here we focus on the development of the combination of oncolytic virotherapy with checkpoint inhibitors designed to target the programmed cell death protein 1 and programmed cell death ligand 1 signaling axis. We also discuss future directions for the clinical application of this novel combination therapy.

• cancer
• immune checkpoint blockade
• immunotherapy
• viral oncolysis

Oncolytic virotherapy is being developed as a promising platform for cancer therapy due to its ability to lyse cancer cells in a tumor-specific manner. Vaccinia virus has been used as a live vaccine in the smallpox eradication program and now is being potential in cancer therapy with a great safety profile. Vaccinia strain Guang9 (VG9) is an attenuated Chinese vaccinia virus and its oncolytic efficacy has been evaluated in our previous study. To improve the tumor selectivity and oncolytic efficacy, we here developed a thymidine kinase (TK)-deleted vaccinia virus based on Guang9 strain. The viral replication, marker gene expression and cytotoxicity in various cell lines were evaluated; antitumor effects in vivo were assessed in multiple tumor models. In vitro, the TK-deleted vaccinia virus replicated rapidly, but the cytotoxicity varied in different cell lines. It was notably attenuated in normal cells and resting cells in vitro, while tumor-selectively replicated in vivo. Significant antitumor effects were observed both in murine melanoma tumor model and human hepatoma tumor model. It significantly inhibited the growth of subcutaneously implanted tumors and prolonged the survival of tumor-bearing mice. Collectively, TK-deleted vaccinia strain Guang9 is a promising constructive virus vector for tumor-directed gene therapy and will be a potential therapeutic strategy in cancer treatment.

• Tian Tan strain Guang9
• cancer therapy
• oncolytic virotherapy
• thymidine kinase
• vaccinia virus

Modern oncotherapy approaches are based on inducing controlled apoptosis in tumor cells. Although a number of apoptosis-induction approaches are available, site-specific delivery of therapeutic agents still remain the biggest hurdle in achieving the desired cancer treatment benefit. Additionally, systemic treatment-induced toxicity remains a major limiting factor in chemotherapy. To specifically address drug-accessibility and chemotherapy side effects, oncolytic virotherapy (OV) has emerged as a novel cancer treatment alternative. In OV, recombinant viruses with higher replication capacity and stronger lytic properties are being considered for tumor cell-targeting and subsequent cell lysing. Successful application of OVs lies in achieving strict tumor-specific tropism called oncotropism, which is contingent upon the biophysical interactions of tumor cell surface receptors with viral receptors and subsequent replication of oncolytic viruses in cancer cells. In this direction, few viral vector platforms have been developed and some of these have entered pre-clinical/clinical trials. Among these, the Vesicular stomatitis virus (VSV)-based platform shows high promise, as it is not pathogenic to humans. Further, modern molecular biology techniques such as reverse genetics tools have favorably advanced this field by creating efficient recombinant VSVs for OV; some have entered into clinical trials. In this review, we discuss the current status of VSV based oncotherapy, challenges, and future perspectives regarding its therapeutic applications in the cancer treatment.

• oncolytic virotherapy
• oncolytic virus
• paediatric practice

Glioblastoma is a highly aggressive and malignant type of cancer that is apoptosis resistant and difficult to cure by conventional cancer therapies. In this regard, an oncolytic adenovirus that selectively targets the tumour tissue and induces tumour cell lysis is a promising treatment option. We designed and constructed a hypoxia-responsive and cancer-specific modified human telomerase reverse transcriptase (H5CmTERT) promoter to drive replication of an oncolytic adenovirus (H5CmTERT-Ad). To enhance the anti-tumour efficacy of H5CmTERT-Ad against malignant glioblastoma, we also generated an H5CmTERT-Ad expressing secretable trimeric tumour necrosis factor-related apoptosis-inducing ligand (H5CmTERT-Ad/TRAIL). H5CmTERT promoter-regulated oncolytic adenoviruses showed cancer-specific and superior cell-killing effect in contrast to a cognate control oncolytic adenovirus replicating under the control of the endogenous adenovirus promoter. The cancer cell-killing effects of H5CmTERT-Ad and H5CmTERT-Ad/TRAIL were markedly higher during hypoxia than normoxia owing to hypoxia responsiveness of the promoter. H5CmTERT-Ad/TRAIL showed more potent anti-tumour efficacy than H5CmTERT-Ad did in a xenograft model of TRAIL-resistant subcutaneous and orthotopic glioblastoma through superior induction of apoptosis and more extensive virus distribution in the tumour tissue. Altogether, our findings show that H5CmTERT-Ad/TRAIL can promote dispersion of an oncolytic adenovirus through robust induction of apoptosis in a highly TRAIL-resistant glioblastoma.

• CAR
• CD46
• Cancer
• Conditionally replicative adenovirus
• Therapy

Decorin (DCN) is a small leucine-rich proteoglycan that plays an important role in the regulation of apoptosis, proliferation, intercellular contact, and cell migration. Here we have investigated the detailed mechanism of apoptotic cell death induced by DCN expression. A marked increase in cytotoxicity was observed for both DCN-expressing replication-incompetent (dE1/DCN) and -competent (dB/DCN) adenoviruses (Ads) compared to the corresponding control Ads. FACS and TUNEL assays revealed that the expression of DCN induced apoptotic cell death. Specifically, the expression and stability of p53 were increased by DCN. In addition, western blot data showed that DCN expression activated mitochondrial apoptosis by increasing the expression level of p53. Similarly, DCN-expressing oncolytic Ads induced a greater antitumor effect in a murine xenograft model compared with control Ads. Tissue staining and western blot data from in vivo experiments demonstrated significantly higher levels of apoptosis in tumor tissues from mice treated with DCN-expressing Ads compared to those treated with control Ads. Collectively, these data support that cell killing effect is enhanced with Ad-mediated DCN expression via the induction of p53-mediated mitochondrial apoptosis, which could be a valuable benefit for antitumor efficacy.

• decorin
• mitochondrial apoptosis
• oncolytic adenovirus
• p53