Oncolytic Viral Therapy for Mesothelioma

Abstract

The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1-2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma.

Keywords: adenovirus; herpes simplex virus type 1; measles virus; mesothelioma; novel; oncolytic; vaccinia virus; virotherapy.

Figure 1

The basic principles of oncolytic virotherapy. (A) Administration is most commonly via direct intratumoral injection rather than systemic intravenous route to avoid viral inactivation in the bloodstream and minimize off-target infection. The pleural location of mesothelioma is particularly amenable to direct injection. (B) Viral infection of cancer cells, followed by replication, leads to cell lysis and dissemination of infection. The use of non-replicating viruses results in lysis to a lesser extent than replicating viruses. Acquired defects of the cancer cells and engineered modifications of the viral genome drive infection selectively toward cancer cells. (C) Viral infection and lysis exposes tumor-associated and viral antigens to the immune system. Antigen-presenting cells process these novel antigens via the major histocompatibility complex for presentation to CD4+ and CD8+ T cells. Cytokine release attracts NK cells. Local tumor cell death is augmented by the immune response. (D) Activated T and NK cells circulate throughout the body and recognize distant tumor cells that express the previously uncovered tumor-associated antigens. Note that the systemic immune response is not dependent on viral oncolysis.

Figure 2

The selective infection of tumor cells by oncolytic viruses. In the normal cell, the response to viral infection involves activation of the type 1 interferon (IFN) and protein kinase R (PKR) pathways, resulting in upregulation of eIF2α and inhibition of viral protein synthesis. The p53 and Rb pathways are also activated. Wild-type viruses are able to inhibit various steps of the antiviral response to allow ongoing replication. For example, the herpes simplex virus (HSV) gene ICP34.5 blocks PKR signaling, and the adenovirus genes E1A and E1B inactivate Rb and p53, respectively. The tumor cell may have a number of acquired defects that allow for preferential infection by oncolytic viruses. An increased expression of cell surface proteins facilitates viral entry, such as herpesvirus entry mediator for HSV type 1 (HSV-1) and CD46 for measles virus. Defective IFN and PKR pathways lead to unimpeded viral protein synthesis. Upregulation of RAS in tumor cells results in PKR pathway inhibition. Modification of viruses can further drive tropism and minimize infection of normal cells. Deletion of the HSV gene ICP34.5 renders the virus unable to inhibit PKR in healthy cells and drives infection toward PKR-deficient tumor cells. Similarly, deletion of the adenovirus E1A or E1B genes leads to preferential infection of p53- and Rb-deficient tumor cells.