Introduction of Measles Virus as Oncolytic Virus
Many cancers are still incurable to modern clinical therapy despite current pharmacological advances. Therefore, there's an unmet need for the development of new, targeted, non-toxic therapeutics. Oncolytic viruses (OVs) are a class of replicating viruses that tendentiously infect and lyse cancer cells without damaging normal tissues. At least 11 viruses, including measles virus (MV), adenovirus, reovirus, and vaccinia virus, are being widely explored and have entered clinical trials to treat many advanced cancers. Measles virus is a member of the genus Morbillivirus under the family Paramyxoviridae of the Mononegavirales. This virus is potentially oncotropic in nature and holds oncolytic properties by syncytia formation. The clinical application of its properties in developing a virotherapeutic vector system is being highlighted by scientific and medical institutions.
Measles Virus
Measles virus is usually round but exhibits pleomorphism, such as the appearance of two or more different modalities in the life cycle of several organisms. It is an enveloped virus with a non-segmented genome and comprises single-stranded RNA of negative polarity. The genome organization of the measles virus shares significant similarity to other members of Paramyxoviridae. It is approximately 16 kilobases long in length and contains six genes encode for eight viral proteins. This genome is encapsulated by nucleoprotein (N), phosphoprotein (P), as well as large protein (L) forming the ribonucleoprotein complex (RNP), which is surrounded by matrix (M) protein. The RNA genome makes up complex with N protein and the arrangement is helical. There's a 52 nucleotide non-coding leader region at the beginning that functions as a transcriptional promoter and there's a 37 nucleotide non-coding trailer region at the end that functions as a transcriptional terminator. Measles virus's envelope glycoproteins, including hemagglutinin (H) and fusion (F) proteins, are responsible for mediating virus attachment and fusion, respectively.
Fig.1 A diagrammatic representation of the measles virus structure. (Bhattacharjee, 2018)
Oncolytic Measles Virus and Virotherapy
Measles is a highly infectious disease that resulted from the measles virus and remains a primary cause of child mortality in many developing countries. The OVs are a subtype of a lytic virus that selectively replicates, clears cancer cells, and spreads within the tumor while leaving normal tissue unharmed. The activities of oncolytic measles virus can reflect the basic biological principles of the virus and the interaction of host-virus in the fight between the pathogen and the immunity, which provides patients a potential and efficacious opportunity to treat measles.
Tab.1 Genetically engineered measles virus used for oncolytic virotherapy. (Bhattacharjee, 2018)
- Biological characteristics and cytopathic effects
- Oncolytic measles virus in clinical trials
The infection of measles virus is triggered by the interaction of its H protein with specific cell surface receptors. The interaction leads to a conformational change that activates the viral F glycoprotein, which mediates the process of membrane fusion at neutral pH to allow the RNP entry into the targeted cell cytoplasm. Subsequently, the expression of H and F proteins on the surface of infected cells induces their fusion with neighboring non-infected cells to facilitate efficient viral spread. This cell-to-cell fusion brings about giant multinucleated cells, termed "syncytia", the cytopathic feature of measles virus infection. Syncytia are metabolically active and their formation is associated with increased virus-mediated cytotoxicity both in vivo and in vitro.
The vaccine strain of measles virus is an agent with an extensive range of oncolytic activities in pre-clinical trials with more evidence of safety and efficacy in early clinical trials. This vaccine has a proven safety record and can be used to perform careful genetic modification in the laboratory. Overexpression of the measles virus receptor (CD46) in several tumor cells is likely to direct the virus to preferentially get into transformed cells and there's rising awareness of the value of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget measles viruses by inserting genes for tumor-specific ligands to antigens and by engineering the virus to express synthetic microRNA targeting sequences, and interfering the virus to the natural viral receptors are attractive measures to promote viral specificity and oncolytic effect. Currently, the measles virus in clinical trials is displaying encouraging preliminary outcomes in myeloma, ovarian cancer, and non-Hodgkin lymphoma.
Reference
- Bhattacharjee, S.; et al. Measles virus: Background and oncolytic virotherapy. Biochem Biophys Rep. 2018, 13: 58-62.