**6. Antitumor vs. Antiviral Immunity**

However, immune stimulation in the context of oncolytic virotherapy may hamper overall efficacy by premature viral clearance [124]. Though conferring a safety advantage, the antiviral immune response and specifically high measles seropositivity in the general population is one of the main reservations against using MeV for oncolytic virotherapy. Therefore, multiple strategies have been devised to circumvent anti-viral immunity. Substitution of the P/V/C and also N and L genes of attenuated oncolytic strains for their wild type counterparts has been shown to dampen the cellular IFN response and increase viral spread [125,126]. These variants resulted in higher progeny titers, increased viral gene expression, and cell killing in presence of interferon or in interferon-competent cells. Mutation of common antibody epitopes in the MeV envelope glycoproteins allows for

evasion of virus neutralization in serum [127]. By exchanging the glycoproteins for their counterparts from a related morbillivirus, canine distemper virus, an envelope chimeric MeV was generated which showed similar replication kinetics and oncolytic properties as unmodified MeV, but was not neutralized by human MeV-immune sera [128]. However, these approaches may compromise safety. As alternatives, different "shielding" approaches have been developed to protect oncolytic MeV from antibody-mediated clearance.

One approach is to employ cell carriers to "deliver" oncolytic MeV to the tumor site. Successful tumor delivery by heterofusion of infected carrier cells and tumor cells was first demonstrated for infected monocytes, endothelial cells, and stimulated human peripheral blood cells. This allowed for effective oncolysis after i.v. or i.p. administration after passive immunization in xenograft models [129]. A range of different cell types have been employed as carriers, including T cells [130], cytokine-induced killer cells [131], mesenchymal stem cells [132], mesenchymal stromal cells [133], and also irradiated myeloma cells [134].

As an acellular shield, the scavenger receptor ligand polyinosinic acid can be used to prevent MeV sequestration by hepatic Kupffer cells after i.v. administration [135]. This was shown to enhance oncolytic efficacy in a nude mouse model. Multi-layer coating with ionic polymers and graphene oxide sheets [136] have also been reported as a means to protect MeV from premature clearance [137]. These modifications did not compromise infection of tumor cells and even enhanced oncolytic effects. Administration of UV-inactivated MeV as a decoy virus has been suggested as a means to sequester antiviral antibodies prior to treatment [138].

Instead of modifying the oncolytic agent, immune modulation in the patient has been envisaged to enable measles virotherapy. Clinically approved multidose cyclophosphamide regimens were shown to dampen both primary and secondary antibody responses to MeV [139]. Although pre-existing immunosuppression in advanced stage cancer and especially low antibody levels in myeloma patients were anticipated, cyclophosphamide was also tested in one cohort of the Phase I trial of MV-NIS for advanced multiple myeloma [75]. Clinical data in this regard are still limited, but so far no clear correlation between antimeasles immunity and therapeutic efficacy has been noted.
