Antigen persistence after antibody-drug conjugates in urothelial carcinoma: implications for CAR-cell target selection
Year: 2026
Type: review
Abstract: Antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-engineered cells can converge on the same surface antigens in urothelial carcinoma (UC) yet depend on distinct biological steps. This creates a central uncertainty after ADC progression: whether failure reflects loss of membrane antigen or a downstream resistance mechanism that a CAR might bypass. We synthesize paired human tissue, molecular-imaging, ADC-resistance and UC-specific CAR-cell studies to examine whether an antigen targeted by a failed ADC remains suitable for cellular therapy. NECTIN4 after enfortumab vedotin (EV) provides the most direct evidence. Membranous expression often decreases between primary and metastatic UC, and serial observations document lesion-specific loss. However, selected post-EV biopsies and resistant models retain NECTIN4; in those models, NECTIN4 CAR T cells remain active. Transporter and payload-resistance studies further support target-independent failure. Evidence for HER2 and TROP2 is less direct but suggests that alternative antigens may remain available when NECTIN4 declines. We therefore propose a resistance-state framework: same-target CAR development requires recent evidence of accessible membrane antigen; target loss or marked heterogeneity favors target switching or multi-target strategies; and unresolved states require biomarker-rich testing. Current evidence does not support a clinical treatment sequence. Instead, it defines the sampling, biomarker and correlative-study requirements needed to make post-ADC CAR trials interpretable.
Source: Neoplasia
Authors: Jiayi Liu, Shaoqiang Xing, Qian Liu
Institutions: Tianjin First Center Hospital, Tianjin Medical University
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,530
OpenAlex ID: W7222832293