Combination Immunotherapy with Inhibitor of Apoptosis (IAP) Antagonists to Treat Neuroblastoma

Abstract

Neuroblastoma is the third most common pediatric cancer. Dinutuximab is a recently approved monoclonal antibody targeting GD2, a ganglioside ubiquitously present on neuroblastoma. Recent studies have shown that αGD2 therapy activates PD1-PDL1 signalling, resulting in the inhibition of its full therapeutic potential. The PD1-PDL1 signalling axis is a cellular checkpoint that inhibits immune responses. The blocking of this interaction has been successful in the treatment of numerous cancers, including in combination with anti-GD2 therapy. The Inhibitor of apoptosis (IAP) proteins are commonly upregulated in cancers and prevent cell death through the inhibition of caspases and through the control of NF-κB activity. Smac mimetic compounds (SMCs) have been designed to target IAP activity, thereby promoting cancer cell death. Here, I used the SMC, LCL161, to improve αGD2 antibody treatment against a GD2+ syngeneic neuroblastoma mouse model. I found that murine cell lines NXS2 and N2a were resistant in vitro to LCL161-mediated apoptosis, despite expressing apoptotic components often silenced in neuroblastoma. In vivo, I observed a slight delay in tumour growth induced by LCL161 and I confirmed an in vivo anti-angiogenic effect of LCL161 through ultrasound imaging and necropsy evaluation. I then combined LCL161 and αGD2 antibody (clone ME361-S2a) treatment and reported a delay in NXS2 subcutaneous tumour growth, which was further potentiated with the addition of an αPD-L1 antibody. With optimization, there is potential for SMCs to be used in combination with αGD2 therapy in GD2+ cancers like neuroblastoma.