**2. Measles Virus Oncotropism**

Measles vaccine strain oncotropism correlates with CD46 overexpression on malignantly transformed cells [23]. Although viral entry occurs in benign cells and at low CD46 receptor density, a certain threshold of expression is required for syncytia formation and cell death [24]. In myeloma, CD46 upregulation has been associated with abnormal p53 [25]. The epithelial receptor for MeV, nectin-4 [26,27], is also a tumor marker which

I.

may render carcinomas of pancreatic [28], colorectal [29], and mammary [30] origin susceptible to MeV oncolysis. Post-transcriptional regulation of nectin-4 levels by miR-31 and miR-128 has been demonstrated in breast cancer and glioblastoma [31]. In certain EBV-associated B cell lymphomas, viral latency may promote upregulation of the MeV receptor CD150/SLAM [32]. On the post-entry level, the cellular interferon (IFN) response has been identified as a key determinant of sensitivity to oncolytic MeV across several tumor entities, including the NCI60 panel of cancer cell lines [33]. In adult T cell leukemia/lymphoma, resistance to MeV oncolysis was associated with IFN-β production, while sensitive cells did not produce IFN [34]. In mesothelioma and melanoma, effects of treatment with oncolytic MeV were found not to correlate with CD46 expression, but rather with defects in the IFN re-

128 has been demonstrated in breast cancer and glioblastoma [31]. In certain EBV-associated B cell lymphomas, viral latency may promote upregulation of the MeV receptor

*Cancers* **2021**, *13*, x 3 of 19

CD150/SLAM [32].

On the post-entry level, the cellular interferon (IFN) response has been identified as a key determinant of sensitivity to oncolytic MeV across several tumor entities, including the NCI60 panel of cancer cell lines [33]. In adult T cell leukemia/lymphoma, resistance to MeV oncolysis was associated with IFN-β production, while sensitive cells did not produce IFN [34]. In mesothelioma and melanoma, effects of treatment with oncolytic MeV were found not to correlate with CD46 expression, but rather with defects in the IFN response [35,36]. Consistently, expression of retinoic acid inducible gene I (RIG-I) and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) [37] and IFN-induced transmembrane protein 1 (IFITM1) [38] have been suggested as correlates of relative resistance to MeV oncolysis. Kurokawa et al. have devised a gene expression signature designating constitutive IFN pathway activation to predict outcome of oncolytic MeV treatment [39]. Further, RSAD2/viperin, encoded by an IFN-stimulated gene (ISG), has been shown to inhibit release of MeV progeny in ovarian cancer models [40]. sponse [35,36]. Consistently, expression of retinoic acid inducible gene I (RIG-I) and IFNinduced protein with tetratricopeptide repeats 1 (IFIT1) [37] and IFN-induced transmembrane protein 1 (IFITM1) [38] have been suggested as correlates of relative resistance to MeV oncolysis. Kurokawa et al. have devised a gene expression signature designating constitutive IFN pathway activation to predict outcome of oncolytic MeV treatment [39]. Further, RSAD2/viperin, encoded by an IFN-stimulated gene (ISG), has been shown to inhibit release of MeV progeny in ovarian cancer models [40]. Aside from the cellular antiviral response, several additional cellular factors have been associated with sensitivity to MeV oncolysis. For instance, apoptosis regulators appear to play a role. Caspase 3 has been implicated in MeV-induced cancer cell death [41,42] and overexpression of Bcl-2 reduces MeV-induced cell death in B cell lymphomas [43]. More broadly, basic cellular processes such as protein translation are necessary for effi-

Aside from the cellular antiviral response, several additional cellular factors have been associated with sensitivity to MeV oncolysis. For instance, apoptosis regulators appear to play a role. Caspase 3 has been implicated in MeV-induced cancer cell death [41,42] and overexpression of Bcl-2 reduces MeV-induced cell death in B cell lymphomas [43]. More broadly, basic cellular processes such as protein translation are necessary for efficient MeV replication and thus tumor cell killing. Stimulating cellular translation by insulin-like growth factor-I (IGF-I) or forced expression of eIF4E increases efficacy of oncolytic MeV, while inhibitors of cap-dependent translation reduce MeV oncolysis [44]. Furthermore, it has been reported that integrity of lipid rafts is a prerequisite for oncolysis with the MV-Hu191 strain [21]. Determinants of MeV oncotropism are summarized in Figure 2. cient MeV replication and thus tumor cell killing. Stimulating cellular translation by insulin-like growth factor-I (IGF-I) or forced expression of eIF4E increases efficacy of oncolytic MeV, while inhibitors of cap-dependent translation reduce MeV oncolysis [44]. Furthermore, it has been reported that integrity of lipid rafts is a prerequisite for oncolysis with the MV-Hu191 strain [21]. Determinants of MeV oncotropism are summarized in Figure 2. Overall, oncolytic MeV acts via mechanisms distinct from other established cancer treatments. Accordingly, gemcitabine-resistant pancreatic adenocarcinoma cells are susceptible to MeV oncolysis [45] and chemotherapy-induced senescence does not abrogate oncolysis [46].

**Figure 2.** Measles virus oncotropism. Oncolytic measles virus (MeV) does not replicate productively in normal cells (left) in contrast to cancer cells (right). This oncotropism has been associated with differential expression of i.a. the depicted host cells factors. ISG: interferon-stimulated gene; RIG-I: retinoic acid-inducible gene I; IGF-1: insulin-like growth factor-**Figure 2.** Measles virus oncotropism. Oncolytic measles virus (MeV) does not replicate productively in normal cells (**left**) in contrast to cancer cells (**right**). This oncotropism has been associated with differential expression of i.a. the depicted host cells factors. ISG: interferon-stimulated gene; RIG-I: retinoic acid-inducible gene I; IGF-1: insulin-like growth factor-I.

**3. Combination Therapies**  Nevertheless, monotherapy with oncolytic MeV will often be insufficient to cure advanced stage malignancies. Modern medical oncology builds on effective combination Overall, oncolytic MeV acts via mechanisms distinct from other established cancer treatments. Accordingly, gemcitabine-resistant pancreatic adenocarcinoma cells are susceptible to MeV oncolysis [45] and chemotherapy-induced senescence does not abrogate oncolysis [46].
