Evidence gaps and route-dependent development requirements for CAR cellular therapy in urothelial carcinoma: a systematic evidence map and public-data analysis
- 1The First Central Clinical College of Tianjin Medical University
- 2Department of Urology, Tianjin First Central Hospital
Abstract
Background: Chimeric antigen receptor (CAR)-engineered cells are being investigated for urothelial carcinoma, but evidence requirements for antigen selection and local or systemic delivery remain undefined. We asked whether any target or route can presently be prioritised.
Methods: We combined a systematic evidence map and registry audit with secondary analysis of public bulk and single-nucleus transcriptomes and normal-tissue resources. In GSE169379, infercnvpy used same-object non-epithelial reference cells; epithelial nuclei with high copy-number variation (CNV-high) scores were defined as those above the 99th percentile of reference scores. Aggregate rankings were replaced by two evidence gates: antigen eligibility and then product- and route-specific exposure validation. No new participants or experiments were included.
Results: All 13 peer-reviewed primary studies were preclinical; none reported a treated patient with urothelial carcinoma. Five registry programmes were retained without bladder-specific results; the only urothelial-specific record changed from recruiting to terminated. Among 21,756 sampled epithelial nuclei from the 29,974-nucleus GSE169379 tumour object, 1,828 were classified CNV-high using 8,218 non-epithelial nuclei from the same object as the reference. Across 18 evaluable patients, median detection fractions were 0.083 for NECTIN4, 0.169 for ERBB2, 0.229 for CD44, 0.267 for EGFR, 0.385 for PSCA and 0.093 for MUC16; corresponding medians in four normal-urothelial batches were 0.290, 0.401, 0.423, 0.598, 0.527 and 0.008. These unpaired cross-object RNA contrasts do not establish a therapeutic window. Equal-dose intravesical MUC16-directed CAR T cells outperformed intravenous administration in two orthotopic xenograft models and showed bladder-localised exposure, but this single programme cannot establish a general route advantage or human safety.
Conclusions: No evaluated target meets requirements for unqualified clinical prioritisation. Epitope-matched malignant-cell surface expression and functional normal-tissue safety should precede testing whether a specific route achieves the exposure required by the intended disease distribution. Current route evidence is product-specific and preclinical.
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BibTeX
@article{liu2026evidence,
title = {{Evidence gaps and route-dependent development requirements for CAR cellular therapy in urothelial carcinoma: a systematic evidence map and public-data analysis}},
author = {Jiayi Liu and Zhibiao Guo and Jinke Guo and Shaoqiang Xing and Qian Liu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1941701},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1941701/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Evidence gaps and route-dependent development requirements for CAR cellular therapy in urothelial carcinoma: a systematic evidence map and public-data analysis
AU - Jiayi Liu
AU - Zhibiao Guo
AU - Jinke Guo
AU - Shaoqiang Xing
AU - Qian Liu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1941701
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1941701/full
AB - Background: Chimeric antigen receptor (CAR)-engineered cells are being investigated for urothelial carcinoma, but evidence requirements for antigen selection and local or systemic delivery remain undefined. We asked whether any target or route can presently be prioritised. Methods: We combined a systematic evidence map and registry audit with secondary analysis of public bulk and single-nucleus transcriptomes and normal-tissue resources. In GSE169379, infercnvpy used same-object non-epithelial reference cells; epithelial nuclei with high copy-number variation (CNV-high) scores were defined as those above the 99th percentile of reference scores. Aggregate rankings were replaced by two evidence gates: antigen eligibility and then product- and route-specific exposure validation. No new participants or experiments were included. Results: All 13 peer-reviewed primary studies were preclinical; none reported a treated patient with urothelial carcinoma. Five registry programmes were retained without bladder-specific results; the only urothelial-specific record changed from recruiting to terminated. Among 21,756 sampled epithelial nuclei from the 29,974-nucleus GSE169379 tumour object, 1,828 were classified CNV-high using 8,218 non-epithelial nuclei from the same object as the reference. Across 18 evaluable patients, median detection fractions were 0.083 for NECTIN4, 0.169 for ERBB2, 0.229 for CD44, 0.267 for EGFR, 0.385 for PSCA and 0.093 for MUC16; corresponding medians in four normal-urothelial batches were 0.290, 0.401, 0.423, 0.598, 0.527 and 0.008. These unpaired cross-object RNA contrasts do not establish a therapeutic window. Equal-dose intravesical MUC16-directed CAR T cells outperformed intravenous administration in two orthotopic xenograft models and showed bladder-localised exposure, but this single programme cannot establish a general route advantage or human safety. Conclusions: No evaluated target meets requirements for unqualified clinical prioritisation. Epitope-matched malignant-cell surface expression and functional normal-tissue safety should precede testing whether a specific route achieves the exposure required by the intended disease distribution. Current route evidence is product-specific and preclinical.
SN - 1664-3224
ER -