The following is a summary of “DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy,” published in the May 2024 issue of Oncology by Su et al.
Deltalike ligand 3 (DLL3) plays a pivotal role as an inhibitory ligand, modulating Notch signaling and exhibiting upregulation facilitated by ASCL1, a prominent transcription factor in the SCLC-A subtype of small-cell lung cancer (SCLC). Therapeutic strategies targeting DLL3 encompass a diverse array, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Despite initial promise demonstrated in a phase II trial, rovalpituzumab tesirine (Rova-T) faltered in subsequent phase III trials, prompting the discontinuation of its development. Conversely, DLL3-targeted BiTEs have garnered substantial clinical interest, exemplified by tarlatamab, which exhibited heightened response rates and prolonged progression-free survival in a phase II trial.
Notably, its biologics license application (BLA) is under rigorous review by the US Food and Drug Administration (FDA). A multitude of ongoing phase III investigations seek to elucidate further the clinical efficacy of tarlatamab, concurrently with the development of innovative DLL3-targeted T-cell engagers spanning both bispecific and trispecific modalities. Emerging CAR-T cell therapies directed at DLL3 undergo meticulous preclinical and early-phase clinical evaluations. Furthermore, preclinical endeavors have unveiled promising efficacy for DLL3-targeted radiotherapy, leveraging β-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. The landscape of DLL3-targeted therapies holds significant promise for the management of SCLC.
Future clinical trials will pivotally compare treatment outcomes across various modalities and explore synergistic combination therapies to optimize patient survival outcomes.
Source: molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02012-z