can-22-1433_supplementary_movies2b_suppsm2b.mov (6.15 MB)

Supplementary MovieS2b from Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer

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posted on 2023-03-31, 06:00 authored by Jonathan Chou, Emily A. Egusa, Sinan Wang, Michelle L. Badura, Fei Lee, Anil P. Bidkar, Jun Zhu, Tanushree Shenoy, Kai Trepka, Troy M. Robinson, Veronica Steri, Jiaoti Huang, Yuzhuo Wang, Eric J. Small, Emily Chan, Bradley A. Stohr, Alan Ashworth, Brant Delafontaine, Sylvie Rottey, Keegan S. Cooke, Nooshin Hashemi Sadraei, Brian Yu, Mark Salvati, Julie M. Bailis, Felix Y. Feng, Robert R. Flavell, Rahul Aggarwal

Supplemental Movies 2a-2c: 22Rv1-NuclightGreen and SHP-77-NuclightRed mixed population co-cultures. Time-lapse movies of 22Rv1 cells (labeled with NuclightGreen) and SHP-77 cells (labeled with NuclightRed) co-cultured with T cells. Both the 22Rv1 and SHP-77 cells were plated at equal densities and treated with either NT control BiTE®, AMG 757, or the PSMA-targeting HLE BiTE, AMG 160. T cells were added to each well at an E:T ratio of 10:1. Images were captured every 4 hours at 4x magnification for 5 days. a. 22Rv1, SHP-77, and T cells co-cultured with NT control BiTE®. b. 22Rv1, SHP-77, and T cells co-cultured with AMG 757. c. 22Rv1, SHP-77, and T cells co-cultured with AMG 160.

Funding

Prostate Cancer Foundation (PCF)

U.S. Department of Defense (DOD)

Canadian Institutes of Health Research (IRSC)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Amgen (Amgen Inc)

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ARTICLE ABSTRACT

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.

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cancer

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