Overview
Oncolytic Immunotherapy
Oncolytic immunotherapy represents a novel immunotherapeutic approach to treating cancer based on the selective targeting of tumour cells by viruses. Both native and genetically modified viruses are used to selectively infect tumour cells, leading to tumour cell death and the activation of systemic immune responses[1]. The ability of viruses to kill cancer cells has been known to scientists for over 50 years, but only in the last few decades have viruses been explored as a cancer therapy [2]. The main mechanism of action of oncolytic viruses is based on the ability for viruses to infect and replicate within a cell. Once sufficient viral replication has occurred, lysis of the cell can be initiated, allowing the virus to infect nearby cells, spreading the infection in an exponential fashion [1]. In this sense, this novel therapy exploits the sheer evolutionary power of viruses, allowing us to turn cancer cells into anti-cancer factories. In addition, a number of oncolytic therapies carry the gene for cytokines such as Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) which allow for the infected cancer cells to express proteins that stimulate immune cells which can aid in elimination of the cancer [3]. A number of viruses have been developed to be used in oncolytic therapies, with many of these viruses currently undergoing advanced stage clinical trials. FDA approval for a number of therapies is expected within the coming years, with the T-VEC therapy by Amgen expected to be one of the first to be approved. Update: On 10/27/2015, The FDA advisory board voted 22-1 in favour of granting approval to T-VEC for use in the United States; more information can be found here
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Bypassing the Defence:
Oncolytic Viruses avoid anti-viral pathways in cancer cells ![]() The series of molecular changes that allow the proliferative advantage in cancer cells can be exploited with oncolytic viruses. Cancer cells have a variety of mutations that weaken, and often inactivate the anti-viral responses found in normal cells. For example, many cancer cells have mutations that down regulate innate immune response proteins such as RIG-1, IRF7 and IRF3 [1]. These proteins are normally responsible for the detection of viral particles within cells. Upon detection, they activate pathways which lead to the clearance of viral particles, and whole-cell anti-viral response. Cancer cells that down regulate these proteins are unable to clear the viral particles, allowing the virus to replicate within the cancer cell. This allows for viral therapies to specifically target cancer cells as cancer cells will be unable to clear the virus through immune response. Additionally, normal cells express Type I Interferons in response to viral infection which can activate pro-apoptotic pathways leading to cell death and clearance of the virus. Many cancer cells are deficient in Type I Interferons, and most cancers gain resistance to programmed cell death, allowing viral infection and replication [5]. This image represents a few of the molecular pathways that can be exploited by oncolytic viruses for selective infection of cancer cells.
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Exploiting an Advantage:
Oncolytic Viruses attack Oncogenic pathways. ![]() Oncogenic pathways, often involving the expression of an oncogene, or the loss of a tumour suppressor give tumour cells their ability to bypass normal cellular regulation. Oncolytic viruses exploit these very oncolytic pathways to induce cell death in tumour cells. One particular pathway often exploited by cancer cells is the Ras pathway. Ras proteins are over-expressed in a large proportion of cancers. Ras proteins are involved in a number of signalling pathways, many of which lead to resistance to cell death and increased proliferation - two key mechanisms in carcinogenesis [9]. In normal cells, protein kinase R (PKR) induces a signalling pathway that protects the cell from viral infection. In cells with over-expressed Ras, PKR activity is inhibited, allowing viral infection. This pathway is exploited by oncolytic viruses such as Reovirus which are normally cleared by PKR [10]. B-cell Lymphoma (BCL-2) family proteins that confer apoptotic resistance are also commonly over-expressed in cancers. These proteins give the cancer cells a survival advantage - they inhibit programmed cell death. This advantage in cancer cells can be exploited by targeting the cell with Newcastle Disease Virus (NDV). NDV has a relatively long incubation time. Since cancers with excess BCL-2 are resistant to apoptosis, NDV will be given enough time to incubate in these cancer cells, allowing it to replicate and kill the cancer [11].
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Gaining entry:
Oncolytic viruses exploit a variety of mechanisms to enter their target cells. ![]() Due to the wide range genomic changes in cancer cells, and in particular, the genetic changes that allow for metastasis in malignant cancers, cancer cells are capable of expressing a wide range of cell surface receptors and adhesion proteins. These proteins are often over-expressed. Viruses often gain entry into the cell by interacting with cell surface proteins such as receptors or adhesion proteins. Other cell-entry mechanisms such as receptor-mediated endocytosis can also be exploited [6]. HSV-1 therapy uses the Herpesvirus Entry Mediator for entry into cells. This receptor is over expressed in melanoma and various carcinomas, allowing HSV-1 to gain entry into these types of cancer cells [7]. Viruses can also be engineered to target specific cell surface receptors expressed in cancer cells. For example, measles virus has been engineered to selectively target carcinoembryonic antigen (CEA), an antigen that is only expressed on certain adenocarcinomas [8]. The graphic represents a few of the common mechanisms that can be targeted by viral therapies for entry into cancer cells.
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Recruiting Natural Defences:
Oncolytic Viruses activate Systemic Anti-Cancer Immune Response
Oncolytic Viruses activate Systemic Anti-Cancer Immune Response
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Oncolytic viruses are capable of activating the body's natural defences against disease by inducing systemic, anti-cancer immunity. Upon infection with a virus, cancer cells induce anti-viral responses that consist of an increase in the production of Reactive Oxygen Species (ROS), the release of chemokines and and the release of cytokines, particularly those in the Interferon family. These compounds stimulate immune cells such as antigen presenting cells, CD8+ T cells and Natural Killer cell.s Upon lysis of the cancer cells by the oncolytic virus, further immune response is initiated as Danger-Associated Molecular Patterns (DAMPs), Pathogen-Associated Molecular Patterns (PAMPs) and Tumour-Associated Antigens (TAAs), are recognized by immune cells [1]. The released DAMPs and PAMPs bind to receptors on immune cells, and stimulate their aactivityThe released TAAs, are taken up and displayed by Antigen-Presenting Cells (APCs), this leads to further activation of T cells which are capable of killing cancer cells. The importance of CD8+ T cell activation in removing cancer cells has been demonstrated clinically, and is one of the powerful mechanisms recruited by oncolytic viral therapies [12]. Natural Killer cells, cells that are a part of the innate immune system, are capable of recognizing the lack of Major Histocompatibility Complex I (MHC I). MHC I is a protein that is expressed on all nucleated cells, allowing the body to distinguish its normal cells (those bearing MHC I) from abnormal and foreign cells (those without MHC I) [13]. Upon activation by the release of signals from the infected cancer cell, Natural Killer cells can recognize the lack of MHC I on cancer cells, and induce cell death [14].