Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

Keywords: AMG 757; Antibody-drug conjugate; BiTE; DLL3; Rovalpituzumab tesirine; Small cell lung cancer; T-cell engager; Tarlatamab.

Fig. 1

DLL3 expression in normal and tumor tissue. DLL3 protein expression via immunostaining (brown color) in A normal pancreatic tissue and B an SCLC tumor section [114]. Staining for DLL3 expression shows weak expression with a cytoplasmic pattern of localization in normal human pancreatic tissue sections (Panel A) and strong membranous and cytoplasmic expression in human SCLC (Panel B). Arrows in Panel A point to pancreatic islet cells. Blue hematoxylin counterstain is used to visualize cell nuclei. Original objective, ×200. DLL3 delta-like ligand 3; SCLC small cell lung cancer

Fig. 2

Mechanism of action of Rova-T. A Binding of Rova-T to cell surface DLL3 triggers receptor-mediated endocytosis and B internalization of the Rova-T–DLL3 complex followed by fusion with the late endosome. C PBD is released from the Rova-T complex following enzymatic cleavage within the lysosome. The released PBD intercalates between double-stranded nuclear DNA in a site-specific manner and causes DNA damage, which ultimately leads to D apoptosis [17]. ADC antibody-drug conjugate, DLL3 delta-like ligand 3, PBD pyrrolobenzodiazepine, Rova-T rovalpituzumab tesirine

Fig. 3

Mechanism of action of A TCEs and B–E structure of DLL3-targeting TCEs in development. Panel A depicts a generic structure for T-cell engagers, although it should be noted that Fc regions are not a feature of all DLL3-targeting T-cell engagers. The structures of the newer DLL3-targeting T-cell engagers RO7616789 and PT217 have not yet been published. CD cluster of differentiation; DLL3 delta-like ligand 3, Fab fragment antigen-binding, Fc fragment crystallizable, scFv single-chain variable fragment, TAA tumor-associated antigen, TCE T-cell engager, TCR T-cell receptor