Search

Prostate cancer is traditionally considered an immunologically “cold” tumor type rendering patients insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent anti tumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumors are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a sub-optimal therapeutic index. Our target discovery and validation efforts identified STEAP2 as a superior prostate antigen for therapeutic targeting. Importantly, STEAP2 is a highly prevalent prostate cancer antigen displaying high, homogeneous cell surface expression across all stages of disease. A novel lead generation approach facilitated the development of a potent and specific armored STEAP2 CAR-T therapeutic candidate, AZD0754. This second generation CAR-T product is armored with a dominant-negative TGFβRII, thereby bolstering activity in the TGFβ-rich immunosuppressive environment of prostate cancer. Armored STEAP2 CAR-T cells demonstrate favorable in vitro properties, robust dose dependent in vivo efficacy in STEAP2 expressing cell line- and patient derived- mouse xenograft models and encouraging preclinical safety. Taken together, this data builds confidence in the specificity and potency of this potential first in class STEAP2 targeted CAR-T therapy and supports future clinical development. Citation Format: Dewald van Dyk, Peter Zanvit, Christine Fazenbaker, Kelly McGlinchey, Weichuan Luo, Jessica Pezold, John Meekin, Chien-ying Chang, Benjamin Clark, Philip L. Martin, Clare Hoover, Eric Tu, Ryan Gilbreth, Mark Cobbold, Gordon Moody, Emily E. Bosco. Antitumor activity of AZD0754, a dnTGFbRII armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB085.