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

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

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 6

Effect of enhanced CAR-T manufacturing on antitumor activity.

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Effect of enhanced CAR-T manufacturing on antitumor activity. (A) 40A3Bz...
(A) 40A3Bz dnTGFβRII CAR-Ts were manufactured according to the SMART process, and CAR positivity, activation, and phenotype of the cells were evaluated at expansion day 4 and compared with those of untransduced T cells from the same donor. (B) Bioenergetic profile of SMART (day 4) versus traditional (day 11) manufactured 40A3Bz dnTGFβRII CAR-Ts as determined by Seahorse analysis. OCR, oxygen consumption rate; ECAR, extracellular acidification rate. (C) 40A3Bz dnTGFβRII SMART CAR-Ts were dosed at 4 concentrations (0.3 × 106, 1 × 106, 3 × 106, and 6 × 106 CAR-positive cells) by tail vein injection in NSG MHC class I/II knockout mice implanted with 22Rv1 cells overexpressing TGF-β (n = 10). Tumor volumes and body weights were measured to 50 days after tumor implantation. (D) PDX fragments from frozen stocks of various prostate cancer PDX models were implanted into NSG MHC I/II knockout mice and randomized when tumor volumes for each model ranged from 125 to 250 mm3. Mice were dosed as described in C with 0.5 × 106 or 5 × 106 40A3Bz dnTGFβRII SMART CAR-Ts and compared with 5 × 106 untransduced SMART controls (n ranged from 4 to 12 depending on the model). The IHC data inset on each model represents the cell surface STEAP2 expression scoring. (E) Serum levels of IFN-γ across all PDX models described in D, determined by MSD (n = 4 or greater). Experiments are representative of 2 different donor CAR-Ts. Data in A–C are representative of multiple independent experiments prepared from 3 healthy donors, while D and E were performed once with material from 1 donor. All data represent mean ± SEM.