• adenovirus
• herpes simplex virus
• myxoma virus
• oncolytic virus
• ovarian cancer
• vaccinia virus
• vesicular stomatitis virus
• virus

• Humans
• Oncolytic Virotherapy/methods
• Female
• Ovarian Neoplasms/therapy
• Ovarian Neoplasms/immunology
• Oncolytic Viruses/immunology
• Animals
• Immune Checkpoint Inhibitors/therapeutic use
• Combined Modality Therapy/methods

• Editorial
• Hepatocellular carcinoma
• Immunotherapeutic
• Oncolytic virus
• Virotherapy

• G47Δ
• head and neck cancer
• immunotherapy
• local recurrence
• neoadjuvant therapy
• oncolytic virus therapy
• squamous cell carcinoma
• teserpaturev
• tongue cancer
• tumor microenvironment

• MMR vaccine
• glioblastoma
• oncolytic viruses
• virotherapy

• IG2017-20699 Italian Association for Cancer Research

• clinical trials
• immunotherapy
• recurrent glioma

• 20HXBH170 West China Hospital of Sichuan University

• GSC
• cancer stem cell
• glioblastoma
• immunotherapy
• oHSV
• oncolytic virus
• virotherapy

• Humans
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Simplexvirus/genetics
• Oncolytic Virotherapy/methods
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Neoplasm Recurrence, Local/therapy
• Tumor Microenvironment

• R01 CA160762 NCI NIH HHS
• National Institutes of Health

• vaccines
• infectious diseases

• Animals
• Humans
• Viral Vaccines/genetics
• Viral Vaccines/therapeutic use
• Genetic Vectors
• Orthomyxoviridae/genetics
• Communicable Diseases
• Adenoviridae/genetics

• convection-enhanced delivery
• drug delivery
• glioma
• immunotherapy

• T35 AG044303 NIA NIH HHS
• NIH/NCI
• NIH/NINDS

• G47Δ
• focal adhesion kinase inhibitor
• immune checkpoint inhibitor
• oncolytic virus therapy
• pancreatic ductal adenocarcinoma
• teserpaturev
• tumor microenvironment
• tumor stroma

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 10⁸ pfu (low dose) or 1 × 10⁹ pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development.

G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma.

Malignant soft tissue tumors, particularly highly malignant leiomyosarcomas, are resistant to chemotherapy and associated with a poor prognosis. T-01, a third-generation genetically modified herpes simplex virus type 1, replicates in tumor cells alone and exerts a cell-killing effect. The current study aimed to investigate the antitumor effect of T-01, which is a novel treatment for leiomyosarcoma. In vitro, six human cell lines and one mouse sarcoma cell line were assessed for T-01 cytotoxicity. In vivo, the efficacy of T-01 was examined in subcutaneously transplanted leiomyosarcoma (SK-LMS-1) cells and subcutaneously or intraperitoneally transplanted mouse sarcoma (CCRF S-180II) cells. Cytokines were assessed using ELISpot assay with splenocytes from the allogeneic models for immunological evaluation. T-01 showed cytotoxicity in all seven cell lines (p < 0.001). In the SK-LMS-1 xenotransplantation model, tumor growth was suppressed by T-01 administration (p = 0.02). In the CCRF S-180II subcutaneous tumor model, bilateral tumor growth was significantly suppressed in the T-01-treated group compared with the control group (p < 0.001). In the peritoneal dissemination model, T-01 treatment caused significant survival prolongation compared with the control (p < 0.01). In conclusion, third-generation genetically modified herpes simplex virus type 1 may be an effective novel therapy against refractory sarcomas.

• 4T1
• CT26
• Combined therapy
• Oncolytic herpes simplex virus

• Advanced melanoma
• clinical trials
• combination therapy
• immune checkpoint inhibitors
• local therapy
• melanoma
• metastatic melanoma
• regional therapy
• systemic therapy

• clinical
• combination therapy
• mechanism
• neuroblastoma
• oncolytic virus
• preclinical

Treatment options are limited for esophageal carcinoma (EC). G47Δ, a triple-mutated, conditionally replicating herpes simplex virus type 1 (HSV-1), exhibits enhanced killing of tumor cells with high safety features. Here, we studied the efficacy of G47Δ using preclinical models of human EC. In vitro, G47Δ showed efficient cytopathic effects and replication capabilities in all eight human esophageal cancer cell lines tested. In athymic mice harboring subcutaneous tumors of human EC (KYSE180, TE8, and OE19), two intratumoral injections with G47Δ significantly inhibited the tumor growth. To mimic the clinical treatment situations, we established an orthotopic EC model using luciferase-expressing TE8 cells (TE8-luc). An intratumoral injection with G47Δ markedly inhibited the growth of orthotopic TE8-luc tumors in athymic mice. Furthermore, we evaluated the safety of applying G47Δ to the esophagus in mice. A/J mice inoculated intraesophageally or administered orally with G47Δ (10⁷ plaque-forming units [pfu]) survived for more than 2 months without remarkable symptoms, whereas the majority with wild-type HSV-1 (10⁶ pfu) deteriorated within 10 days. PCR analyses showed that the G47Δ DNA was confined to the esophagus after intraesophageal inoculation and was not detected in major organs after oral administration. Our results provide a rationale for the clinical use of G47Δ for treating EC.

• G47Δ
• biodistribution
• esophageal cancer
• esophageal squamous cell carcinoma
• herpes simplex virus
• intraesophageal inoculation
• oncolytic virus therapy
• orthotopic tumor model
• preclinical safety
• teserpaturev

The prognosis of oral squamous cell carcinoma (OSCC) largely depends on the control of lymph node metastases. We evaluate the therapeutic efficacy of G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), in mouse tongue cancer models. Intratumoral injection with G47Δ prolonged the survival in all orthotopic models investigated. In both athymic and immunocompetent models, G47Δ injected into the tongue cancer swiftly traffics to the draining cervical lymph nodes and suppresses lymph node metastases. In the immunocompetent KLN205-MUC1 model, in which the metastatic cascade that tongue cancer patients commonly experience is reproduced, intratumoral G47Δ injection even immediately prior to a tumor resection prolonged survival. Cervical lymph nodes 18 h after G47Δ treatment showed the presence of G47Δ infection and an increase in CD69-positive cells, indicating an immediate activation of T cells. Furthermore, G47Δ injected directly into enlarged metastatic lymph nodes significantly prolonged the survival at an advanced stage. Whereas intratumorally injected oncolytic HSV-1 does not readily circulate in the blood stream, G47Δ is shown to traffic in the lymphatics swiftly. The use of G47Δ can lead to entirely new treatment strategies for tongue cancer and other OSCC at all clinical stages.

• G47Δ
• antitumor immunity
• herpes simplex virus type 1
• lymph node metastasis
• neoadjuvant therapy
• oncolytic virus therapy
• oral squamous cell carcinoma
• orthotopic tumor model
• tongue cancer
• viral trafficking

• CTLA-4
• G47Δ
• PD-1
• antitumor immunity
• esophageal carcinoma
• herpes simplex virus type 1
• immune-checkpoint inhibitors
• oncolytic virus therapy
• regulatory T cells
• tumor microenvironment

Herpes simplex virus (HSV) can be genetically altered to acquire oncolytic properties so that oncolytic HSV (oHSV) preferentially replicates in and kills cancer cells, while sparing normal cells, and inducing anti-tumor immune responses. Over the last three decades, a better understanding of HSV genes and functions, and improved genetic-engineering techniques led to the development of oHSV as a novel immunovirotherapy. The concept of in situ cancer vaccination (ISCV) was first introduced when oHSV was found to induce a specific systemic anti-tumor immune response with an abscopal effect on non-injected tumors, in the process of directly killing tumor cells. Thus, the use of oHSV for tumor vaccination in situ is antigen-agnostic. The research and development of oHSVs have moved rapidly, with the field of oncolytic viruses invigorated by the FDA/EMA approval of oHSV talimogene laherparepvec in 2015 for the treatment of advanced melanoma. Immunovirotherapy can be enhanced by arming oHSV with immunomodulatory transgenes and/or using them in combination with other chemotherapeutic and immunotherapeutic agents. This review offers an overview of the development of oHSV as an agent for ISCV against solid tumors, describing the multitude of different oHSVs and their efficacy in immunocompetent mouse models and in clinical trials.

• cancer vaccine
• herpes simplex virus
• immunotherapy
• oncolytic virus

• Animals
• Biological Products
• Herpes Simplex/genetics
• Herpesvirus 1, Human
• Humans
• Immunotherapy/methods
• Melanoma
• Mice
• Neoplasms/prevention & control
• Neoplasms/therapy
• Oncolytic Virotherapy/methods
• Oncolytic Viruses
• Transgenes
• Vaccination

• R01 CA160762 NCI NIH HHS
• R01 NS032677 NINDS NIH HHS

One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host’s immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival.

• M1/M2 phenotypic shift
• anti-tumour immunity
• cancer immunotherapy
• innate immune system
• oncolytic virotherapy
• tumour microenvironment
• tumour-associated macrophages

• Animals
• Clinical Trials as Topic
• Humans
• Immunity, Innate
• Macrophages/immunology
• Mice
• Neoplasms/immunology
• Neoplasms/therapy
• Oncolytic Virotherapy
• Phagocytosis
• Tumor Microenvironment/immunology

• oncolytic virus
• car-nk cells
• immunotherapy
• gbm
• combination therapy

• Animals
• Apoptosis
• CD8-Positive T-Lymphocytes/immunology
• Cell Proliferation
• Combined Modality Therapy
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Glioblastoma/immunology
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Glioblastoma/therapy
• Humans
• Interleukin-15/genetics
• Interleukin-15/metabolism
• Interleukin-15 Receptor alpha Subunit/genetics
• Interleukin-15 Receptor alpha Subunit/metabolism
• Killer Cells, Natural/immunology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Oncolytic Virotherapy/methods
• Oncolytic Viruses/genetics
• Receptors, Chimeric Antigen/immunology
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• R01 AI129582 NIAID NIH HHS
• R01 CA185301 NCI NIH HHS
• R01 NS106170 NINDS NIH HHS
• T32 CA186895 NCI NIH HHS
• R21 CA223400 NCI NIH HHS
• R01 CA068458 NCI NIH HHS
• R35 CA210087 NCI NIH HHS
• P01 CA163205 NCI NIH HHS
• R37 CA068458 NCI NIH HHS
• R01 CA247550 NCI NIH HHS
• R01 CA265095 NCI NIH HHS
• T32 CA221709 NCI NIH HHS

• Adolescent
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/pathology
• Brain Neoplasms/radiotherapy
• Brain Neoplasms/therapy
• Child
• Child, Preschool
• Combined Modality Therapy
• Female
• Glioma/diagnostic imaging
• Glioma/pathology
• Glioma/radiotherapy
• Glioma/therapy
• Humans
• Kaplan-Meier Estimate
• Killer Cells, Natural
• Leukocyte Count
• Male
• Oncolytic Virotherapy/adverse effects
• T-Lymphocytes

• UL1 TR003096 NCATS NIH HHS
• R01 FD006368 FDA HHS
• P30 CA013148 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 FD005379 FDA HHS

Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations.

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.

• GM-CSF
• T-VEC
• intratumoral immunotherapy
• melanoma
• oncolytic virus
• talimogene laherparepvec

• oncolytic virus
• vaccinia virus
• il-2
• antitumor adaptive immunity
• tumor-specific t cells
• expansion ex vivo
• adoptive t cell therapy

• Animals
• Cell- and Tissue-Based Therapy/methods
• Female
• Humans
• Immunotherapy, Adoptive/methods
• Lymphocytes, Tumor-Infiltrating/immunology
• Mice
• Oncolytic Viruses/immunology

• P30 CA047904 NCI NIH HHS
• R01 CA233521 NCI NIH HHS
• R13 EB033695 NIBIB NIH HHS

• alloantigen
• animal models: murine
• autoantibody
• basic (laboratory) research/science
• cancer/malignancy/neoplasia: melanoma
• heart transplantation/cardiology
• hematology/oncology
• immunosuppression/immune modulation
• translational research/science

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.

• combination therapy
• genetic engineering
• herpes simplex virus
• immune checkpoint inhibitors
• oncolytic immunoviroterapy
• oncolytic virus
• tropism retargeting
• virotherapy
• virus arming

• Combined Modality Therapy/methods
• Combined Modality Therapy/trends
• Herpesvirus 1, Human/genetics
• Herpesvirus 1, Human/metabolism
• Humans
• Oncolytic Virotherapy/methods
• Oncolytic Virotherapy/trends
• Oncolytic Viruses/genetics
• Oncolytic Viruses/metabolism
• Simplexvirus/genetics
• Simplexvirus/metabolism

G47Δ is a triple-mutated oncolytic herpes simplex virus type 1 designed to induce antitumor immune responses efficiently. We examine the usefulness of G47Δ as a neoadjuvant therapy for radiofrequency ablation (RFA), a standard local treatment for certain cancers such as liver cancer, but remote recurrences within the same organ often occur. In A/J mice harboring bilateral subcutaneous Neuro2a tumors, the left tumors were treated with G47Δ intratumoral injections followed by RFA. Whereas the RFA-treated tumors were all eradicated, the growth of the right tumors was evaluated and tumor-infiltrating lymphocytes were analyzed. The G47Δ+RFA treatment caused smaller volumes of right tumors, accompanied by increased CD8⁺/CD45⁺ T cells, compared with G47Δ monotherapy. After depletion of CD8⁺ T cells, the enhanced efficacy on the contralateral tumors was completely abolished. Neoadjuvant G47Δ led to rejection of rechallenged tumors, which was caused by efficient induction of specific antitumor immune responses shown by enzyme-linked immunospot (ELISPOT) assays. Treatment of tumor-harboring animals with an anti-programmed cell death 1 ligand 1 (PD-L1) antibody led to even greater efficacy on contralateral tumors. Our study indicates that the neoadjuvant use of G47Δ effectively enhances the efficacy of RFA via CD8⁺ T cell-dependent immunity that is further augmented by an immune checkpoint inhibitor.

• G47Δ
• Oncolytic virus
• hepatocellular carcinoma
• herpes simplex virus type 1
• immune checkpoint inhibitor
• neoadjuvant
• radiofrequency ablation

• G47Δ
• gastric cancer
• herpes simplex virus type 1
• oncolytic virus therapy
• scirrhous-type gastric cancer

BACKGROUND: Few chemotherapies are available for neuroendocrine tumors, especially for highly malignant neuroendocrine cancers. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 selectively replicates in tumor cells and shows cytotoxicity against tumor cells without damaging surrounding normal tissues. We examined the antitumor effect of T-01 to explore novel treatments for patients with neuroendocrine tumors.

METHODS: The cytotoxicity of T-01 was tested in two human and one murine neuroendocrine tumor cell lines in vitro. Mouse models with subcutaneously implanted human neuroendocrine tumor QGP1 cells were used to investigate T-01 efficacy in vivo.

RESULTS: T-01 showed cytotoxicity against the three cell lines in vitro. In xenograft models, the growth of tumors derived from QGP1 cells was inhibited by T-01 compared with control group. Although weight loss of mice was observed with tumor growth in the control group, it was suppressed by T-01 administration. The antitumor effects of T-01 were dependent on virus concentration and frequency of administration.

CONCLUSIONS: T-01 effectively inhibits tumor cell proliferation in a poorly differentiated NEC mouse model. These results suggest that the third-generation oncolytic HSV-1 may serve as a novel treatment for patients with neuroendocrine tumors.

• herpes simplex virus
• mouse xenograft model
• neuroendocrine tumor
• oncolytic virus

• fusion protein
• fusogenic virus
• oncolytic virotherapy
• syncytia

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications.

This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

This review highlights recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on talimogene laherparepvec in the treatment of advanced melanoma as a model for future solid tumor indications.

• Immune checkpoint inhibitors
• Intratumoral immunotherapies
• Melanoma
• OPTiM
• Talimogene laherparepvec

• Humans
• Immunologic Factors
• Immunotherapy
• Melanoma/therapy
• Oncolytic Virotherapy
• Oncolytic Viruses/genetics

• glioblastoma
• novel treatment
• therapy

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival.

We tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection.

Strong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs.

This is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.

• ATL
• Conditionally replicating adenoviruses
• Survivin

• apoptosis
• canine distemper virus
• canine mammary tubular adenocarcinoma cells
• oncolysis

• 5’UTR
• glioma
• microRNA
• oncolytic herpes virus
• survivin

• adenovirus
• gliomas
• mesenchymal stem cell
• mesenchymal stromal cell

• T cells
• antitumor immunity
• cancer immunotherapy
• oncolytic vaccines
• tumor antigens
• tumor major histocompatibility complex ligandome

• Glioblastoma
• Mathematical model
• Non-linear mixed effects modeling
• Pharmacokinetic/pharmacodynamics modeling
• Treatment score

• Animals
• Cell Enlargement
• Cell Line, Tumor
• Cell Proliferation/physiology
• Humans
• Kinetics
• Models, Theoretical
• Oncolytic Viruses/metabolism
• Tumor Burden/physiology
• Virus Replication/physiology

Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T‐Vec (talimogene laherparepvec), a second‐generation oncolytic herpes simplex virus type 1 (HSV‐1) armed with GM‐CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T‐Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX‐594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM‐CSF‐expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild‐type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third‐generation oncolytic HSV‐1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast‐track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor‐specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients.

• Clinical trial
• G47∆
• herpes simplex virus
• oncolytic immunotherapy
• oncolytic virus

• immune checkpoints
• immunogenic cell death
• melanoma
• senescence

• Animals
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Humans
• Immunologic Factors/therapeutic use
• Immunotherapy
• Neoplasms/immunology
• Neoplasms/therapy

• I01 BX002301 BLRD VA
• K24 CA172355 NCI NIH HHS
• IK6 BX005225 BLRD VA
• K12 CA090625 NCI NIH HHS
• R01 CA034590 NCI NIH HHS
• I01 BX000196 BLRD VA
• P30 CA068485 NCI NIH HHS
• R01 CA116021 NCI NIH HHS

Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system.

• immune
• immunology
• immunotherapy
• large-scale
• oncolytic
• screen
• virus

• Animals
• Humans
• Immunotherapy/trends
• Neoplasms/immunology
• Neoplasms/therapy
• Oncolytic Virotherapy/trends
• Oncolytic Viruses/genetics
• Oncolytic Viruses/physiology

Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy.

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.