Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-01, Vol.83 (2), p.301-315
• Main Authors: Chou, Jonathan, Egusa, Emily A, Wang, Sinan, Badura, Michelle L, Lee, Fei, Bidkar, Anil P, Zhu, Jun, Shenoy, Tanushree, Trepka, Kai, Robinson, Troy M, Steri, Veronica, Huang, Jiaoti, Wang, Yuzhuo, Small, Eric J, Chan, Emily, Stohr, Bradley A, Ashworth, Alan, Delafontaine, Brant, Rottey, Sylvie, Cooke, Keegan S, Hashemi Sadraei, Nooshin, Yu, Brian, Salvati, Mark, Bailis, Julie M, Feng, Felix Y, Flavell, Robert R, Aggarwal, Rahul
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal; Humans; Immunotherapy; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Ligands; Male; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Neuroendocrine Tumors - diagnostic imaging; Neuroendocrine Tumors - pathology; Neuroendocrine Tumors - therapy; Positron-Emission Tomography; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Zirconium
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-22-1433

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. 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.