666. Oncolytic Herpes Virotherapy Induces a Paracrine Death Signal Causing Synergistic Antitumor Efficacy with Aurora A Kinase Inhibition

Aurora A Kinase (AURKA) inhibition with the investigational agent alisertib results in abnormal mitotic progression and the induction of apoptosis in multiple tumor cell lines. Cell cycle arrest is a strategy employed by a variety of viruses, including herpes simplex virus (HSV), to bolster viral reproduction. We previously demonstrated the anti-tumor efficacy of oncolytic HSV and alisertib as monotherapies in models of malignant peripheral nerve sheath tumor (MPNST). We then proceeded to test alisertib and the oncolytic HSV Seprehvir in combination, finding a synergistic anti-tumor effect between the two therapies. Considering this, we hypothesized that alisertib potentiates Seprehvir infection, leading to more rapid and robust viral proliferation with concomitant tumor regression. However, our efforts to quantify enhanced viral infection with combination therapy have uncovered no significant differences in Seprehvir viral growth kinetics witih or without alisertib therapy. Therefore, the synergistic tumor response of Seprehvir combined with alisertib in vitro or in vivo is not due to augmented viral infection. We then hypothesized that Seprehvir infection potentiates the anti-tumor effect of alisertib. In line with this hypothesis, there is a signficant decrease in tumor cell proliferation in alisertib-treated tumor cells that are exposed to soluble factors released by Seprehvir-infected cells. Furthermore, by UV inactivation of Seprehvir conditioned media, we demonstrate that these soluble death signals are not replication competent virus released by infected cells. Taken together, our results suggest a novel mechanism through which Seprehvir-infected cells release a paracrine signal to surrounding cells promoting cell death and increasing the anti-tumor activity of alisertib therapy.