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

Publication ,  Journal Article
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; Yu, B ...
Published in: Cancer Res
January 18, 2023

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 18, 2023

Volume

83

Issue

2

Start / End Page

301 / 315

Location

United States

Related Subject Headings

  • Zirconium
  • Prostatic Neoplasms
  • Positron-Emission Tomography
  • Oncology & Carcinogenesis
  • Neuroendocrine Tumors
  • Mice
  • Membrane Proteins
  • Male
  • Ligands
  • Intracellular Signaling Peptides and Proteins
 

Citation

APA
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MLA
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Chou, J., Egusa, E. A., Wang, S., Badura, M. L., Lee, F., Bidkar, A. P., … Aggarwal, R. (2023). Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer. Cancer Res, 83(2), 301–315. https://doi.org/10.1158/0008-5472.CAN-22-1433
Chou, Jonathan, Emily A. Egusa, Sinan Wang, Michelle L. Badura, Fei Lee, Anil P. Bidkar, Jun Zhu, et al. “Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.Cancer Res 83, no. 2 (January 18, 2023): 301–15. https://doi.org/10.1158/0008-5472.CAN-22-1433.
Chou J, Egusa EA, Wang S, Badura ML, Lee F, Bidkar AP, et al. Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer. Cancer Res. 2023 Jan 18;83(2):301–15.
Chou, Jonathan, et al. “Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.Cancer Res, vol. 83, no. 2, Jan. 2023, pp. 301–15. Pubmed, doi:10.1158/0008-5472.CAN-22-1433.
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. Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer. Cancer Res. 2023 Jan 18;83(2):301–315.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 18, 2023

Volume

83

Issue

2

Start / End Page

301 / 315

Location

United States

Related Subject Headings

  • Zirconium
  • Prostatic Neoplasms
  • Positron-Emission Tomography
  • Oncology & Carcinogenesis
  • Neuroendocrine Tumors
  • Mice
  • Membrane Proteins
  • Male
  • Ligands
  • Intracellular Signaling Peptides and Proteins