Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation.
Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma. We found the enhanced antitumor effect was due to multiple mechanisms that likely each contribute to the combination effect. First, oncolytic herpes virus increased the sensitivity of uninfected cells to alisertib cytotoxicity, a process we term virus-induced therapeutic adjuvant (VITA). Second, alisertib increased peak virus production and slowed virus clearance from tumors, both likely a consequence of it preventing virus-mediated increase of intratumoral NK cells. We also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid derived suppressor cells, which normally are protumorigenic. Our data suggest that clinical trials of the combination of oHSV and alisertib are warranted in patients with neuroblastoma or MPNST.
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Mark A
MA
Currier
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Les
L
Sprague
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, USA.
Tilat A
TA
Rizvi
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Brooke
B
Nartker
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Chun-Yu
CY
Chen
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Pin-Yi
PY
Wang
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Brian J
BJ
Hutzen
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Meghan R
MR
Franczek
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, USA.
Ami V
AV
Patel
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, USA.
Katherine E
KE
Chaney
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.|Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Keri A
KA
Streby
Takeda Pharmaceuticals International Co, Cambridge, MA, USA.
Jeffrey A
JA
Ecsedy
Virttu Biologics, Ltd, Biocity, Scotland, Newhouse, United Kingdom.
Joe
J
Conner
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center; Cincinnati, Ohio, USA.
Nancy
N
Ratner
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.|Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Timothy P
TP
Cripe
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001381:Azepines / Q000008:administration & dosage*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009442:Neurilemmoma / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D011743:Pyrimidines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A
Aurora A kinase; MPNST; neuroblastoma; oHSV