A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

Targeting DLL3 with an antibody-drug conjugate eliminates tumor-initiating cells in high-grade pulmonary neuroendocrine cancers. Not just another Notch Pulmonary neuroendocrine tumors, such as small cell lung cancer, are among the most difficult cancers to treat. Although standard chemotherapy regimens are available for this type of cancer, their effects are only transient, and the tumors typically acquire resistance to the drugs very quickly. Saunders et al. have discovered that DLL3, a ligand in the Notch signaling pathway, is associated with the neuroendocrine cancer phenotype. The authors targeted DLL3 with an antibody conjugated to a cytotoxic drug, which proved to be much more effective than standard chemotherapy for treating patient-derived tumor xenografts. Unlike chemotherapy, the anti-DLL3 treatment appeared to be particularly effective against tumor-initiating cells, which may account for its efficacy. The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.