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Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer
Peter Zanvit, … , Gordon Moody, Emily E. Bosco
Peter Zanvit, … , Gordon Moody, Emily E. Bosco
Published November 15, 2023
Citation Information: J Clin Invest. 2023;133(22):e169655. https://doi.org/10.1172/JCI169655.
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Research Article Oncology Article has an altmetric score of 9

Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer

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Abstract

Prostate cancer is generally considered an immunologically “cold” tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-β type II receptor, bolstering its activity in the TGF-β–rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-β–rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line–derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.

Authors

Peter Zanvit, Dewald van Dyk, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica M. Pezold, John Meekin, Chien-ying Chang, Rosa A. Carrasco, Shannon Breen, Crystal Sao-Fong Cheung, Ariel Endlich-Frazier, Benjamin Clark, Nina J. Chu, Alessio Vantellini, Philip L. Martin, Clare E. Hoover, Kenesha Riley, Steve M. Sweet, David Chain, Yeoun Jin Kim, Eric Tu, Nathalie Harder, Sandrina Phipps, Melissa Damschroder, Ryan N. Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco

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Figure 3

Generation of an anti-STEAP2 antibody that demonstrates specificity in model systems.

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Generation of an anti-STEAP2 antibody that demonstrates specificity in m...
(A) Chimera containing the STEAP3-GS-PDGFRβTM-FLAG amino acid sequence backbone with the sequence of the STEAP2 extracellular loops grafted on to establish cell surface localization. (B) FACS analysis demonstrating robust and stable expression of the STEAP3-2–FLAG chimera and, by extrapolation, the STEAP3-2 (non-tagged) used for antibody generation, at the cell surface of Ad293 cells. (C) 40A3 scFv-Fc was tested for binding to Ad293 cells expressing human STEAP family members (STEAP1, 2, 3, and 4). (D) Multiple scFv-Fcs and full-length IgG1 antibodies were screened for binding to antigen-positive (Ad293 STEAP3-2, Ad293 STEAP3-2 murine, and LNCaP) cells and antigen-negative (Ad293 and LNCaP STEAP2 CRISPR) cell lines. Representative FACS titration graphs show binding curves for the 40A3 scFv-Fc, 40A3 IgG1, and nonbinding IgG1 as a negative control in the LNCaP STEAP2 CRISPR and LNCaP cell lines. Anti–human Fc secondary antibodies conjugated with Alexa Fluor 647 were used for detection of scFv-Fc or IgG1 binding to cells by flow cytometry. (E) Models of STEAP3-STEAP2 ECD chimeras used to assess 40A3 IgG domain recognition. (F) FACS analysis showing preferential binding of 40A3 IgG to ECD2 of STEAP2 on Ad293 cells expressing STEAP3-2 chimeras. All FACS results are representative of n > 3 experimental replicates.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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