73. Effects of the Innate Immune System on Oncolytic Measles Virotherapy

Vaccine strain derived Measles Virus is currently being tested in clinical trials for the treatment of several tumor types. Clinical response to MV therapy can vary, despite similar stages of disease, pre-existing antibody titers and MV entry receptor expression among treated patients. By using Next-Gen Sequencing in tumor samples deriving from ovarian cancer (OvCa) and glioblastoma (GBM) patients who were treated with MV in clinical trials, we observed that expression of interferon-stimulated genes (ISG), such as IFI44, MX1, MX2, RSAD2, and IFI27, correlated with permissiveness to MV infection and clinical outcome. Therefore, we hypothesized that elevated baseline levels of ISG expression directly confers resistance to MV infection in GBM and OvCa patients, and can possibly serve as predictive markers of response to MV therapy. To test this hypothesis we have assessed the baseline ISG expression in 27 primary patient-derived GBM xenograft lines. We found that 4 of the 27 lines have elevated baseline levels of ISG expression. Four primary GBM lines with low baseline levels of ISG expression were infected with MV-NIS (MOI 1 and 0.1). Upon infection, these cells were effectively killed and produced high titers of virus (>104 TCID50/ml by 48hr). In contrast, three primary GBM lines with high baseline levels of ISG expression were resistant to cell killing and produced significantly less virus upon infection with MV-NIS (MOI 1 and 0.1). ISG expression is regulated by the ISGF-3 complex via Stat-1/-2 and Jak-1 activation. Treatment with 3μm of the FDA approved Jak1/2 inhibitor ruxolitinib (Jakafi) for 48hr prior to MV infection (MOI 1 and 0.1) significantly increased MV production and cell killing in the high ISG expressing primary GBM39 line. The observed Jakafi effect is mediated via decreased ISG expression both at baseline and in response to MV infection. Experiments assessing the use of Jakafi in combination with MV in vivo are ongoing. In order to explore an association between ISG expression and MV restriction in OvCa patients, we assessed baseline ISG expression in 118 primary patient-derived ovarian xenograft lines. We found that 57 of the 118 samples have elevated baseline levels of ISG expression. MV therapy in an OvCa xenograft with low baseline levels of ISG expression led to significant prolongation of survival. Ongoing in vivo work in orthotopic ovarian models with variable ISG levels is assessing the association with efficacy of MV therapy. These experiments can lead to elucidation of the role baseline ISG expression plays in controlling response to MV therapy, which could be critical for patient selection and future clinical trial planning. Funding by: Brain SPORE (P50 CA108961), R01 CA154348 and Ovarian SPORE (P50 CA136393)