Neuroblastomas have neuroendocrine features and often show similar gene expression patterns to
small cell lung cancer including high expression of delta-like
ligand 3 (DLL3). Here we determine the efficacy of
rovalpituzumab tesirine (Rova-T), an antibody
drug conjugated (ADC) with a
pyrrolobenzodiazepine (PBD) dimer toxin targeting DLL3, in preclinical models of human
neuroblastoma. We evaluated DLL3 expression in
RNA sequencing data sets and performed immunohistochemistry (IHC) on
neuroblastoma patient derived xenograft (PDX), human
neuroblastoma primary
tumor and normal childhood tissue microarrays (TMAs). We then evaluated the activity of Rova-T against 11
neuroblastoma PDX models using varying doses and schedules and compared anti-
tumor activity to expression levels. DLL3
mRNA was differentially overexpressed in
neuroblastoma at comparable levels to
small cell lung cancer, as well as Wilms and
rhabdoid tumors. DLL3
protein was robustly expressed across the
neuroblastoma PDX array, but membranous staining was variable. The human
neuroblastoma array, however, showed staining in only 44% of cases, whereas no significant staining was observed in the normal childhood tissue array. Rova-T showed a clear dose response effect across the 11 models tested, with a single dose inducing a complete or partial response in 3/11 and stable disease in another 3/11 models. No overt signs of toxicity were observed, and there was no treatment-related mortality. Strong membranous staining was necessary, but not sufficient, for anti-
tumor activity. Rova-T has activity in a subset of
neuroblastoma preclinical models, but heterogeneous expression in these models and the near absence of expression seen in human
tumors suggests that any DLL3-targeting clinical trial should be only performed with a robust companion diagnostic to evaluate DLL3 expression for patient selection.