Stockem, Chantal F. and Gil-Jimenez, Alberto and Ali, Hamza and van Dorp, Jeroen and van Dijk, Nick and van Montfoort, Maurits L. and Alkemade, Maartje and Broeks, Annegien and Seignette, Iris M. and Hooijberg, Erik and Brugman, Wim and Voogd, Rhianne and van Rhijn, Bas W. G. and Mertens, Laura S. and de Feijter, Jeantine M. and Mehra, Niven and van der Heijden, Antoine G. and Meijer, Richard P. and Suelmann, Britt B. M. and Scheper, Wouter and Wessels, Lodewyk F. A. and Vis, Daniel J. and van der Heijden, Michiel S. (2025) Biomarker Analysis and Treatment Dynamics Following Preoperative Ipilimumab plus Nivolumab in Locally Advanced Urothelial Cancer from the Phase IB NABUCCO Study. CLINICAL CANCER RESEARCH, 31 (18). pp. 3897-3906. ISSN 1078-0432, 1557-3265
Full text not available from this repository. (Request a copy)Abstract
Purpose: In NABUCCO, the safety and efficacy of preoperative ipilimumab plus nivolumab were assessed in stage III urothelial cancer. Encouraging responses were achieved, and ipilimumab 3 mg/kg (ipilimumab-high) seemed more effective than ipilimumab 1 mg/kg (ipilimumab-low). We explored ipilimumab plus nivolumab response biomarkers and tumor microenvironment (TME) treatment dynamics.Patients and Methods: Baseline formalin-fixed, paraffin-embedded tumor tissue was analyzed using PD-L1 IHC (n = 51) and whole-exome and transcriptome sequencing (both n = 53) and correlated with response. Baseline infiltration of CD8+ T cells (n = 51) and at cystectomy (n = 42) was examined. Single-cell RNA sequencing (scRNA-seq) of CD3+ T cells was conducted on on-treatment resection tissue of two responders to ipilimumab-high to explore the characteristics of CD8+ T cells within the TME.Results: High tumor mutational burden and PD-L1 positivity were associated with response to ipilimumab plus nivolumab. Nonresponding patients exhibited increased expression of a TGF beta signature. We observed increased transcription of the g2m checkpoint and e2f target in responders to ipilimumab-high and enhanced transcription of IFN-alpha and IFN-gamma hallmarks in responders to ipilimumab-low. CD8+TCF7+ T cells accumulated in the TME of responders to ipilimumab-high. scRNA-seq of CD8A+TCF7+ T cells demonstrated enhanced expression of IL7R, CCR7, GPR15, XCL1, SELL, and LEF1.Conclusions: Our data indicate that tumor mutational burden, PD-L1, and TGF beta are potential biomarkers for response to ipilimumab plus nivolumab in stage III urothelial cancer. An inflammatory TME might be relevant for responding to ipilimumab-low. We found that in responders to ipilimumab-high, TCF7+CD8+ T cells accumulated in the TME. scRNA-seq in two responders suggested that TCF7+CD8A+ T cells express genes associated with immunologic memory formation and T-cell homing.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | OPEN-LABEL; T-CELLS; IMMUNOTHERAPY; MULTICENTER; CARCINOMA; PEMBROLIZUMAB; ATEZOLIZUMAB; CHEMOTHERAPY; CISPLATIN; SURVIVAL; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Apr 2026 11:18 |
| Last Modified: | 17 Apr 2026 11:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67673 |
Actions (login required)
 |
View Item |
