*4.4. Oncolytic Measles Virus*

Oncolytic measles virus (oMV) has been applied in many Phase I/II clinical trials against numerous types of cancers including ovarian cancer, pancreatic cancer and glioblastoma (GBM) [119]. MV is a single-stranded, negative-sense RNA virus that belongs to the Paramyxoviridae family [120]. The entry of MV is mediated by the attachment of the viral Hemagglutinin (H) protein to three known cell surface receptors; the complement regulatory protein CD46, the signaling lymphocyte activating molecule (SLAM) or nectin-4 [121]. The wild type strains of MV mainly bind to the SLAM receptor, the attenuated MV Edmonston's (MV-Edm) vaccine strains enter through CD46 receptor, while nectin-4 can be used by both wild type and Edm strains [121].

The attenuated MV strains have revealed tropism for infecting and killing glioma cells, due to the overexpression of the entry receptor CD46 on the cell surface of these cells [13,122]. Although CD46 is abundantly expressed on glioma cells, facilitating efficient infection, some glioma cell lines show resistance to oncolysis after the viral entry, indicating that other processes can affect its oncolytic efficacy [123].

Indeed, a recent study pinpointed the expression of the interferon-induced transmembrane protein 1 (IFITM1) gene as the responsible ISG for restricting oMV replication in transformed human mesenchymal stromal cells [124]. Additionally, in another study researchers screened eight sarcoma cell lines and found that five of them were susceptible to the oMV. The resistance in the three remaining sarcoma cell lines was attributed to the upregulation of the RIG-I and IFITM1 mRNA expression. Interestingly, it was found that

resistance could be broken by increasing the multiplicity of infection (MOI) in combination with the pro-drug 5-FC [125].

The fact that oMVs are sensitive to antiviral responses was also highlighted by a translational study from Kurokawa et al. [123]. Specifically, it was shown that mice bearing GBM tumors with defective interferon pathway were more responsive to oMV treatment, producing 387-fold higher infectious progeny virions compared to mice bearing GBM with intact interferon pathway. Moreover, gene expression analysis of tumor samples from GBM patients treated with oMV (NCT00390299) showed an inverse correlation of ISGs expression and viral replication [123].

Taken together, evidence suggests that IFITM1 expression may be a biomarker for resistance to oMV virotherapy for GBM patients and could help stratify the patients in oMV trials. Further research needs to be performed in other tumor types to investigate if this is a pan-cancer biomarker for oMV response.
