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Peer-reviewedCC BYNeoplasia: An International Journal for Oncology Research

Antigen persistence after antibody-drug conjugates in urothelial carcinoma: implications for CAR-cell target selection

  • Jiayi Liu1
  • Shaoqiang Xing2
  • Qian Liu3
  1. 1The First Central Clinical College of Tianjin Medical University, No. 24 Fukang Road, Nankai District, Tianjin 300192, China; Department of Urology, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China; Corresponding authors.
  2. 2Department of Urology, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China
  3. 3Department of Urology, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China; Corresponding authors.
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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.

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Cite

BibTeXRIS
BibTeX
@article{liu2026antigen,
  title = {{Antigen persistence after antibody-drug conjugates in urothelial carcinoma: implications for CAR-cell target selection}},
  author = {Jiayi Liu and Shaoqiang Xing and Qian Liu},
  journal = {Neoplasia: An International Journal for Oncology Research},
  year = {2026},
  month = oct,
  doi = {10.1016/j.neo.2026.101383},
  url = {https://doi.org/10.1016/j.neo.2026.101383},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Antigen persistence after antibody-drug conjugates in urothelial carcinoma: implications for CAR-cell target selection
AU  - Jiayi Liu
AU  - Shaoqiang Xing
AU  - Qian Liu
PY  - 2026
DA  - 2026/10/17
JO  - Neoplasia: An International Journal for Oncology Research
DO  - 10.1016/j.neo.2026.101383
UR  - https://doi.org/10.1016/j.neo.2026.101383
AB  - 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.
SN  - 1476-5586
SN  - 1522-8002
ER  -