Oncolytic Viruses in Mesothelioma Treatment
Introduction of Mesothelioma
Mesothelioma is an uncommon malignancy of the parietal and visceral mesothelium. Malignant pleural mesothelioma (MPM) accounts for 90% of cases, as inhalation asbestos exposure is the major risk factor. Typical symptoms of MPM include shortness of breath, chest pain, and weight loss. Characteristic findings on chest imaging are pleural abnormalities, such as a unilateral effusion, calcified plaques, thickening, or masses. Diagnosis often needs a full-thickness pleural biopsy via pleuroscopy or video-assisted thoracoscopy.
Standard Therapy for Mesothelioma
The treatment of mesothelioma is to the extent possible multimodality strategy incorporating surgery, chemotherapy, and radiation. The initial step is evaluating whether the disease is surgically resectable. The two widely employed surgical techniques are extrapleural pneumonectomy (EPP) or the less radical pleurectomy/decortication (P/D), and the surgical approach is determined on a patient-specific basis. Chemotherapy for MPM is recommended for all patients undergoing active therapy, with cisplatin, carboplatin/pemetrexed. In patients not eligible for surgical resection, cisplatin/pemetrexed was shown to have a superior effect compared to cisplatin monotherapy. The addition of bevacizumab to cisplatin/pemetrexed may offer further benefit, increasing overall survival. The role of radiation therapy is less clear, with most studies evaluating its use in the postoperative setting to reduce the risk of local recurrence.
Oncolytic Viral Therapy for Mesothelioma
- Adenovirus
- Oncolytic HSV-1
- Vaccinia Virus
- Measles Virus (MV)
- Vesicular Stomatitis Virus (VSV)
- Newcastle Disease Virus (NDV)
A non-enveloped virus with a linear, double-stranded DNA genome, adenovirus is one of the most widely studied oncolytic viruses. Favorable characteristics are a stable genome (~38 kb, allowing for multiple modifications), non-integration, and high-titer production. Adenovirus for mesothelioma includes both preclinical and clinical studies. Herpes simplex virus (HSV)-thymidine kinase suicide gene inserted into a replication-deficient adenoviral vector (Ad.HSVtk) has been proved successful in animal models. Replication-deficient adenovirus has also been studied as a vector for cytokine gene therapy to counter the immune tolerance characteristic of mesothelioma. Moreover, a series of preclinical studies using conditionally replicating adenoviruses (CRAds), replication-competent oncolytic viruses with modifications to improve tumor selectivity, have shown anti-mesothelioma activity. An in vitro study inserted a midkine promoter overexpressed in tumor cells and demonstrated effective oncolysis in human MPM cell lines. Besides, several CRAd modifications, such as promoters linked to E1 gene expression, viral capsid alterations, and insertion of GFP for viral imaging has been used in vivo studies with murine models. Clinical studies using adenoviral vectors began relatively quickly following preclinical experiments. Focusing on stimulating an immune response, several clinical trials have been completed using an adenoviral vector for gene transfer of IFNβ (Ad.IFNβ). Moreover, replication-incompetent adenovirus expressing IFNα2b (Ad.IFNα2b) has been used in phase I gene therapy. Furthermore, an oncolytic adenovirus (Ad5-D24-GM-CSF) modified for tumor selectivity and with the insertion of a transgene for GM-CSF to augment immune response have been evaluated and no serious adverse events occurred.
An enveloped, double-stranded DNA virus, HSV-1 has a large 152 kb genome. About 30 kb of the genome is non-essential, allowing space for insertion of transgenes. A preclinical study evaluated the replication-competent, neuroattenuated HSV-1716 as oncolytic virotherapy for mesothelioma. Neuroattenuation was achieved by the deletion of both γ134.5 genes encoding the protein ICP34.5. The virus efficiently replicated in and lysed human mesothelioma cells in vitro. No viral dissemination was detected in non-tumor tissue after the mice were given HSV-1716 by intraperitoneal injection. Another preclinical study evaluated three different replication-competent oncolytic herpesviruses: G207, NV1020, and NV1066. For G207, there is the deletion of both γ134.5 genes along with the inactivation of the ICP6 gene for additional attenuation in non-replicating tissues. NV1020 has deletions encoding the genesICP0, ICP4, latency-associated transcripts, one copy of γ134.5 and UL24. NV1066 has single copy deletions of ICP0, ICP4, and γ134.5, plus the addition of GFP for viral imaging.
An enveloped, double-stranded DNA virus in the Poxviridae family, vaccinia virus has a large ~190 kb genome that facilitates insertion and deletion modifications to improve oncolytic efficacy. A study evaluated the vaccinia virus as adjuvant therapy following surgery in a murine model of malignant peritoneal mesothelioma. An oncolytic strain with deletions in thymidine kinase and vaccinia growth factor genes for tumor selectivity was used, named the double-deleted vaccinia virus (vvDD). A single intraperitoneal dose of vvDD prolonged survival compared to controls.
MV is an enveloped RNA virus with a small ~15 kb genome. Given its proven safety profile and natural tumor specificity, the attenuated Edmonston strain is used for oncolytic virotherapy. Other favorable characteristics of MV are a stable genome and cytoplasmic replication. Several preclinical studies with MV in MPM have been completed. The first in vitro experiment used the live attenuated Schwartz strain to evaluate the oncolytic activity and immune response against human mesothelioma cells and normal mesothelial cells. Although in vitro, these results were encouraging for MV-stimulating antitumor immunogenicity. A murine model of mesothelioma was used to study Edmonston strain MV with the insertion of the IFNβ and NIS genes (MV-mIFNβ-NIS). These pathological findings correlated with median survival. Moreover, a peritoneal mesothelioma mouse model showed similar improvements in survival for each virus.
VSV is an RNA virus in the Rhabdoviridae family and it has no known pathogenesis in humans. This virus lacks pre-formed immune response, which is an advantage when introducing VSV as an oncolytic virus. Recombinant VSV engineered to express IFNβ (VSV-IFNβ) augments both the antiviral defense in healthy tissue and the immune response against tumor cells. Several preclinical studies have evaluated VSV-IFNβ against mesothelioma. A murine model of subcutaneous and intraperitoneal tumors injected with VSV-IFNβ has shown reduced tumor growth and increased survival compared to controls.
NDV is enveloped and has a negative-sense, single-stranded RNA genome of approximately 15 kb. This virus causes serious disease in fowl but only mild disease in humans. Similar to VSV, the tumor specificity of NDV is dictated through a defective type I IFN pathway in tumor cells. A preclinical study in mesothelioma with NDV engineered to express GFP showed effective oncolysis against multiple mesothelioma cell lines in vitro. Animals receiving multiple treatments had decreased tumor burden and long life. A phase I trial using a replication-competent NDV enrolled 79 patients with advanced solid malignancies, including 2 cases of mesothelioma. A posttreatment tumor biopsy showed active NDV replication.
Reference
- Pease, D.F.; Kratzke, R.A. Oncolytic viral therapy for mesothelioma. Frontiers in oncology. 2017, 7:179.