432. Aurora A Kinase Inhibition Enhances Oncolytic Herpes Simplex Virotherapy in Models of Neuroblastoma

Neuroblastoma, a heterogeneous tumor that arises from the neural crest, is the most common extracranial solid tumor in children. Fewer than half of patients with high-risk features survive long-term, despite multi-modal therapy with surgery, chemotherapy, antibody therapy, retinoic acid, high-dose chemotherapy, and autologous hematopoietic progenitor cell transplant. We previously reported neuroblastoma xenograft models were responsive to direct intratumoral injection of oncolytic Herpes Simplex Viruses (Parikh et al., Ped Blood Can 44:469, 2005; Mahller et al., Can Res 68:1170, 2008). We have confirmed these findings using an oncolytic HSV, Seprehvir (HSV1716), which is in clinical trials that include pediatric patients (NCT00931931, NCT02031965). The models showed wide variability, however, with CHP134 being highly responsive (4/8 complete responses (CR), 4/8 maintained complete responses (MCR)), CHLA-20 intermediately responsive (4/7 partial responses (PR), 3/7 MCR), SKNBE(2) somewhat responsive (6/7 PR, 1/7 MCR) and SK-N-AS minimally responsive (3/7 progressive disease (PD), 4/7 delayed progression (PD1), 0/7 PR). Because DNA viruses are highly dependent on normal nuclear machinery for DNA synthesis/replication and virus packaging/assembly, we postulated that increased transit time in mitosis may be beneficial to an oncolytic DNA virus. Aurora A Kinase is an enzyme critical for formation of centrioles and mitotic spindles during mitosis and is often dysregulated in cancer. The selective AAK inhibitor, Alisertib (MLN8237), arrests cells in G2/M and is highly effective in neuroblastoma models, making it an attractive candidate for combination studies with Seprehvir. We administered repeated 7-day cycles of combination therapy (10 mg/kg Alisertib once daily by gavage, days 1-5; 10e7 pfu Seprehvir day 5) to mice bearing SK-N-AS xenografts and found significant antitumor synergy (2/10 PD1, 4/10 SD, 2/10 PR, 2/10 CR). Our preliminary data assessing kinetics of virus infection suggest that Alisertib pretreatment enhances virus uptake and spread, accounting for the combinatorial effects. Overall, our findings support clinical testing of Alisertib combined with Seprehvir in patients with refractory neuroblastoma.