DLL3: an emerging target in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.

Keywords: Antibody-drug conjugate (ADC); Bispecific T cell engager (BiTE®) antibody construct; Chimeric antigen receptor (CAR) T cell therapy; Delta-like ligand 3 (DLL3); Immuno-oncology therapy; Neuroendocrine; Small cell lung cancer (SCLC); Targeted therapy.

Fig. 1

DLL3-targeted investigational products utilize distinct mechanisms of action. a Rovalpituzumab tesirine is a DLL3-targeted antibody-drug conjugate (ADC) that consists of a humanized DLL3-specific IgG1 monoclonal antibody, a pyrrolobenzodiazepine (PDB) dimer toxin, and a protease-cleavable linker that covalently links the antibody to the toxin. Internalization of the ADC to lysosomes leads to the cleavage of the linker, release of the toxin, and apoptosis. b AMG 757 is a half-life extended bispecific T cell engager (HLE BiTE®) antibody construct that consists of a single-chain (sc) Fv domain that binds DLL3, an scFv domain that binds CD3ε (an invariable part of the T cell receptor complex), and a fragment crystallizable (Fc) region. AMG 757 is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce serial lysis of tumor cells and concomitant proliferation of T cells. c AMG 119 is an adoptive cellular therapy that consists of a patient’s own T cells that have been genetically modified ex vivo to express a chimeric antigen receptor (CAR) that targets DLL3 and redirects cytotoxic T cells to DLL3-positive cells. AMG 119 is designed to expand and persist in vivo and induce apoptosis of tumor cells