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This journal is a member of and subscribes to the principles of the Committee on Publication Ethics. Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells.
JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. The US Food and Drug Administration approved the biological license application for Amgen’s Imlygic (talimogene laherparepvec) in October 2015. After participating in a brain research study, Steven Keating avidly collected and examined his personal medical data. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation.
The Need for Non-Attenuated Cancer-Specific Oncolytic HSVsMore than twenty years have passed since a herpes simplex virus (HSV) was assayed for the first time in the experimental therapy of human glioblastomas, with the aim of killing the tumor cells and reducing the tumor burden [1]. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. These are mostly black or brown in colour, but can also be pink, red, purple, blue or white. Tumors on the right side in C3H mouse were given 1 × 106 plaque-forming units (PFUs) of RH2. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. This complex increases the phosphorylation state of RB, causing it to release the transcription factor E2F.
The current standard of treatment for malignant gliomas is surgery to remove as much of the tumor as possible, often followed by chemotherapy and radiation.
Antonio Chiocca, Chair of the Department of Neurosurgery and Co-Director of the Institute for the Neurosciences at Brigham and Women’s Hospital, describes a promising new approach called oncolytic virotherapy.
Subsequent efforts were aimed at improving the safety profile, by reducing the intrinsic virulence of the virus. Nine days after the first injection, tumors of the RH-injected right side (a, b) and those of uninjected left side (c, d) were subjected to histological examination and the sections were stained with hematoxylin and eosin. In essence, safety was obtained at the expense of virulence through single or multiple deletions [2]. From scourge to cure: Tumour-selective viral pathogenesis as a new strategy against cancer.
Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms.
Under the HoodBehavior, Neuroscience & Your Brain What Brain Hacks Can Psychologists Teach Us? Studies of the herpes simplex virus type 1 have shown that the virus invades tumor cells and destroys them, while also stimulating the immune system to create a vaccine-like effect against the tumor. Most frequently, the oncolytic HSVs are deleted in the neurovirulence gene ?134.5, and gain cancer specificity from the fact that a number of cancer cells are defective in mounting the innate protein kinase R (PKR) response to the virus [3,4]. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors’ binding sites. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Herpes simplex virus (HSV)1 strains with mutations in UL39 or TK genes, and vaccinia viruses with mutations in TK59, 60 take advantage of the upregulation of this pathway in tumour cells to promote their own DNA synthesis and viral replication1, 51, 52, 54, 57, 72, 91, 96, 101, 136, 137. Arming HSV with therapeutic genes merits further investigation for potential clinical application. Loss of p16 or RB function, and the subsequent release of E2F, can be therapeutically exploited by engineering E2F-responsive promoters upstream of viral genes. These viruses have been and still are being tested in clinical trials [7,8,9,10,11,12,13,14,15,16,17,18], for a review [19,20,21]. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture.
The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells.
Viruses were safely administered intratumorally at doses up to 3 ? 109 plaque forming units (PFU) [12].
Synergistic action of oncolytic herpes simplex virus and radiotherapy in pancreatic cancer cell lines. The adenoviral protein E1A binds to RB, freeing E2F to activate transcription and promote viral replication. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. In general, they exhibit a high safety profile and exert antitumor activity against a variety of tumor types [21]. Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours—Evaluation of a potentially effective clinical therapy. 5-fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer.


Rabkin and coworkers [22] engineered a replication-competent attenuated HSV expressing interleukin 12 (IL-12), designed to induce local and systemic antitumor immunity and favor a Th1 response. Markert, Gillespie and Whitley engineered HSV recombinants deleted in the ?134.5 gene and expressing IL-12, IL-4 or IL-10 [23,24]. A phase 1 trial to test the efficacy of the IL-12-encoding virus in glioblastoma patients is now ongoing (ClinicalTrials.gov identifier NCT02062827). Coffin and coworkers engineered the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) in a ??134.5 virus (OncoVEXGM?CSF), to enhance dendritic cell recruitment and boost the host immune response against the tumor [25]. The herpes simplex virus gE-gI complex facilitatescell-to-cell spread and binds to components of cell junctions.
In a phase III clinical trial, the patients with metastatic melanoma lesions who received repeated intratumoral inoculations of the virus, later renamed talimogene laherparepvec (T-VEC), showed a statistically significant increased durable response rate and an increased overall survival (slightly statistically not significant), when compared to the patients that received subcutaneous injections of GM-CSF alone [26]. Food and Drug Administration approved this product for the treatment of melanoma lesions in the skin and lymph nodes [27], and the European Medicine Agency recommended it. Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice.
The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1.
A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Oncolytic herpes simplex virus 1 encoding 15-prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Herpes simplex type I (HSV-1) infection of the nervous system: is an immune response a good thing?
Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir.
Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer. Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes.
Phase Ib trial of mutant herpes simplex virus G207 inoculated pre- and post-tumor resection for recurrent GBM.
A herpes simplex virus type 1 mutant with gamma 34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice. A herpes simplex virus type 1 mutant deleted for gamma34.5 and LAT kills glioma cells in vitro and is inhibited for in vivo reactivation. Conditionally replicating herpes simplex virus mutant, g207 for the treatment of malignant glioma: Results of a phase I trial. Anti-tumor effect of oncolytic herpes simplex virus G47delta on human nasopharyngeal carcinoma. Potential for efficacy of the oncolytic herpes simplex virus 1716 in patients with oral squamous cell carcinoma. Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures. Oncolytic herpes simplex virus vector g47delta in combination with androgen ablation for the treatment of human prostate adenocarcinoma. Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses.
Efficacy of oncolytic herpesvirus NV1020 can be enhanced by combination with chemotherapeutics in colon carcinoma cells. Intravesical oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and Nv1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model. A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer. Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model.
Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Pilot study of oncolytic viral therapy using mutant herpes simplex virus (HF10) against recurrent metastatic breast cancer.
Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer. Intratumoral injection of herpes simplex virus HF10 in recurrent head and neck squamous cell carcinoma. Both R-VG803 and R-VG809 infected J-HER2 cells, and the infection was blocked by trastuzumab—the MAb to HER-2 from which the scFv was derived. Impact of novel oncolytic virus HF10 on cellular components of the tumor microenvironment in patients with recurrent breast cancer.
In contrast to R-VG803, R-VG809 failed to infect J-nectin-1, or J-HVEM cells, as well as a panel of HER-2-negative human and animal cells, as expected.
Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma.


HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival.
OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Systemic Delivery of Retargeted Oncolytic HSVs by Means of Carrier CellsThe ideal route of delivery for oncolytic viruses in humans carrying metastatic disease is the systemic one. Viruses belonging to different species exhibit intrinsic differences in their ability to spread through the systemic route. A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus. Furthermore, given that the majority of systemically administered oncolytic viruses are rapidly cleared by parenchymal organs and inactivated by non-specific and specific defense systems, it may be very difficult, and most likely unsafe, to reach the high blood concentrations required to achieve the locally active concentrations. Antitumor effects of two newly constructed oncolytic herpes simplex viruses against renal cell carcinoma.
In a phase I clinical trial, the delivery through hepatic artery was safe and showed some efficacy [15,75,76].A recent approach to circumvent delivery obstacles envisions the use of carrier cells, which package the viral cargo and deliver it to the tumor. An oncolytic virus derived from type 2 herpes simplex virus has potent therapeutic effect against metastatic ovarian cancer.
Initial studies employed irradiated tumor cells, which have not been pursued because of safety concerns [77,78,79,80]. Effective treatment of pancreatic cancer xenografts with a conditionally replicating virus derived from type 2 herpes simplex virus. They accumulate within the tumor stroma because of hypoxic conditions and of tumor-associated expression of inflammatory chemokines. A limit is that the cancer-specificity of the oncolytic viruses may prevent infection of these cells.
Induction of strong antitumor immunity by an HSV-2-based oncolytic virus in a murine mammary tumor model. In addition, the adoptively transferred mesenchymal stem cells might contribute to feed the tumor.
So far, mesenchymal stem cells have been assayed as a carrier of oncolytic HSV only in a few studies for intraperitoneal delivery or for local delivery to brain tumors [79,81,82,83,84,85,86,87].The use of mesenchymal stem cells as carriers of retargeted oncolytic viruses has not been attempted, likely because these cells exhibit scarse-null expression of the targeted receptors. Coadministration of a herpes simplex virus-2 based oncolytic virus and cyclophosphamide produces a synergistic antitumor effect and enhances tumor-specific immune responses. Recently, we reported that mesenchimal stromal cells (MSCs) from different sources can be forcedly infected with an HER2-retargeted oncolytic HSV, by exposing the virion-MSC mixtures to the fusogenic agent PEG 6000 [57].
We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v.
Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. The highest concentration of carrier-cells and of viral genomes was in the lungs, the organs where the viral and cellular genomes accumulated at higher amounts for anatomical reasons.
Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells.
The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment also significantly inhibited breast cancer metastases to the brain in the NOD scid gamma mice, and reduced by more than one-half the metastatic burden in the brain [57].
We did not detect any increase in tumor burden in mice treated with uninfected MSCs, ruling out major side effects of MSC administration in mice. Combination of mutated herpes simplex virus type 1 (G207 virus) with radiation for the treatment of squamous cell carcinoma of the head and neck. Treatment of cholangio-carcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy. Radiation therapy potentiates effective oncolytic viral therapy in the treatment of lung cancer. Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase. Functional interaction between fluorodeoxyuridine-induced cellular alterations and replication of a ribonucleotide reductase-negative herpes simplex virus.
Combination of a second generation genetically modified herpes simplex virus 1 (HSV1) with paclitaxel in the treatment of breast cancer in vitro.
Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms. Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12.
Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells.



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