Abstract 4823: CDH3-targeted ADC and CAR-T immunotherapies for metastatic double-negative prostate cancer and triple-negative breast cancer

Abstract Double-negative prostate cancer (DNPC) and triple-negative breast cancer (TNBC) are two challenging malignancies characterized by frequent metastasis and resistance to current therapies. Among them, DNPC may share similar traits with basal-like prostate cancer. These aggressive cancer subtypes demand new treatment strategies. This study investigates CDH3 (P-cadherin), a cell adhesion molecule, as a new target for antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T-cell immunotherapeutics. We conducted comprehensive in silico analysis and confirmed the enriched expression of CDH3 in DNPC and metastatic TNBC. We hypothesize that CDH3-positive (CDH3+) prostate and breast cancer cells will be effectively targeted and eradicated using anti-CDH3 immunotherapeutics in vitro and in vivo. Both anti-CDH3 ADC and CAR-T cell therapies were developed and they both demonstrated significant target-specific cytotoxicity against CDH3high DU145 and MDA-MB-468 cell lines, while sparing CDH3low and CDH3-/- cell lines, highlighting their selectivity in vitro. In vivo efficacy was further validated using NOD-SCID mice engrafted with prostate and breast cancer cell lines in an experimental metastasis setting, where treatment with ADC or CAR-T therapy significantly reduced metastasis burden. Notably, CAR-T therapy, in combination with anti-PD-1 therapy, exhibited enhanced therapeutic potential.This study establishes the robust target-specific cytotoxicity of anti-CDH3 ADC and CAR-T therapies against the most virulent subtypes of metastatic prostate and breast cancers in vitro and in vivo, paving the way for potential clinical development of these therapeutic agents in patients with metastatic DNPC and TNBC. Citation Format: Guoqiang Liu, Shiyu Wang, Loan Duong, Xin Lu. CDH3-targeted ADC and CAR-T immunotherapies for metastatic double-negative prostate cancer and triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4823.