Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.
Journal Article (Journal Article)
UNLABELLED: Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.
- Chou, J; Egusa, EA; Wang, S; Badura, ML; Lee, F; Bidkar, AP; Zhu, J; Shenoy, T; Trepka, K; Robinson, TM; Steri, V; Huang, J; Wang, Y; Small, EJ; Chan, E; Stohr, BA; Ashworth, A; Delafontaine, B; Rottey, S; Cooke, KS; Hashemi Sadraei, N; Yu, B; Salvati, M; Bailis, JM; Feng, FY; Flavell, RR; Aggarwal, R
- January 18, 2023
Volume / Issue
- 83 / 2
Start / End Page
- 301 - 315
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States