{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:58:04Z","timestamp":1780901884065,"version":"3.54.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Patients with la\/mUC have an unfavorable prognosis and limited treatment options, particularly those who were considered ineligible for cisplatin-containing therapeutic schedule. ICIs have played a significant therapeutic role among this group of patients. Ongoing clinical investigations continue to explore the utility of ICIs, both used alone or in combination with other treatment methods.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The purpose of this clinical trial is to explore the efficacy and safety of gemcitabine combined with tislelizumab as initial treatment for the la\/mUC patients who are intolerant to platinum-based drugs. Primary endpoints were ORR and DCR. Secondary endpoints comprised PFS and OS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At the data cutoff (September 1, 2025), 30 patients were enrolled. As the results display, the mPFS was 13.9 months (95% CI: 11.4\u201316.3), and the mOS was 23.3 months ([IQR]: 14.4\u201333.1; 95% CI: 18.2\u201328.3).The confirmed ORR was 46.7% (14\/30; 95% CI: 28.3\u201365.7), DCR was 76.7%. The most frequent TRAEs were hematological toxicities, including leukopenia (43.3%) and neutropenia (40.0%). We also explored the predictive potential of tumor-associated TLS as an innovative analysis. There was a quantitative difference in ORR according to the results of TLS analysis, with response rates of 66.7% (n=9) in TLS positive group and 35.3% (n=17) in negative group. However, this observed change did not reach statistical significance (P\u00a0=\u00a00.218).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In conclusion, the combination of tislelizumab and gemcitabine demonstrated manageable tolerability and a promising preliminary efficacy signal as first-line therapeutic strategy for la\/mUC patients who cannot receive cisplatin-containing regimen and warrants further investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.chictr.org.cn\/index.html<\/jats:ext-link>\n                      , identifier ChiCTR2200061631.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1824893","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:03:59Z","timestamp":1780898639000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tislelizumab combined with gemcitabine as first-line treatment in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma: a single center, single-arm phase 2 trial"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengyao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]},{"name":"Rare Tumors Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Huaiyin, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengjun","family":"Liu","sequence":"additional","affiliation":[{"name":"Rare Tumors Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Huaiyin, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"Rare Tumors Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Huaiyin, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[{"name":"Rare Tumors Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Huaiyin, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qibing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Oncology, the First Affiliated Hospital of Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Rare Tumors Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Huaiyin, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31314","article-title":"Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA","volume":"124","author":"Agarwal","year":"2018","journal-title":"Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.eururo.2020.05.042","article-title":"European association of urology guidelines on upper urinary tract urothelial carcinoma: 2020 update","volume":"79","author":"Roupret","year":"2021","journal-title":"Eur Urol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119920109","article-title":"Aristolochic acid-associated urothelial cancer in Taiwan","volume":"109","author":"Chen","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3109\/0886022x.2016.1155392","article-title":"Higher risk of urothelial carcinoma in the upper urinary tract than in the urinary bladder in hemodialysis patients","volume":"38","author":"Hsiao","year":"2016","journal-title":"Ren Fail"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0090-4295(02)01529-7","article-title":"Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan","volume":"59","author":"Yang","year":"2002","journal-title":"Urology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2011.34.8433","article-title":"Treatment of patients with metastatic urothelial cancer \"unfit\" for Cisplatin-based chemotherapy","volume":"29","author":"Galsky","year":"2011","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2017.07.036","article-title":"European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update","volume":"73","author":"Roupret","year":"2018","journal-title":"Eur Urol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2011.37.3571","article-title":"Randomized phase II\/III trial assessing gemcitabine\/carboplatin and methotrexate\/carboplatin\/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986","volume":"30","author":"De Santis","year":"2012","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"192","DOI":"10.3390\/cancers12010192","article-title":"Current status and future perspectives of immunotherapy for locally advanced or metastatic urothelial carcinoma: A comprehensive review","volume":"12","author":"Kim","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.01213","article-title":"Long-term outcomes in KEYNOTE-052: Phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer","volume":"38","author":"Vuky","year":"2020","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/s0140-6736(16)32455-2","article-title":"Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial","volume":"389","author":"Balar","year":"2017","journal-title":"Lancet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2312117","article-title":"Enfortumab Vedotin and Pembrolizumab in untreated advanced urothelial cancer","volume":"390","author":"Powles","year":"2024","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1200\/jco.22.01643","article-title":"Enfortumab Vedotin plus Pembrolizumab in previously untreated advanced urothelial cancer","volume":"41","author":"Hoimes","year":"2023","journal-title":"J Clin Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1159\/000532127","article-title":"Urological tumor: A narrative review of tertiary lymphatic structures","volume":"107","author":"Shen","year":"2023","journal-title":"Urol Int"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink","year":"2020","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1906-8","article-title":"B cells are associated with survival and immunotherapy response in sarcoma","volume":"577","author":"Petitprez","year":"2020","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/pap.0000000000000161","article-title":"Assessing tumor infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv Anat Pathol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.08.034","article-title":"Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin-unfit patients with advanced urothelial carcinoma: a randomised phase II study (COACH, KCSG GU10-16)","volume":"127","author":"Park","year":"2020","journal-title":"Eur J Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.08.033","article-title":"Vinflunine\/gemcitabine versus carboplatin\/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM)","volume":"127","author":"Holmsten","year":"2020","journal-title":"Eur J Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(17)30616-2","article-title":"First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study","volume":"18","author":"Balar","year":"2017","journal-title":"Lancet Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2022.2124691","article-title":"The efficacy and safety of first-line treatment in cisplatin-ineligible advanced upper tract urothelial carcinoma patients: a comparison of PD-1 inhibitor and carboplatin plus gemcitabine chemotherapy","volume":"11","author":"Huang","year":"2022","journal-title":"Oncoimmunology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/s1470-2045(25)00158-5","article-title":"Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study","volume":"26","author":"Gupta","year":"2025","journal-title":"Lancet Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.03.001","article-title":"ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma","volume":"35","author":"Powles","year":"2024","journal-title":"Ann Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2024.0024","article-title":"NCCN guidelines(R) insights: bladder cancer, version 3.2024","volume":"22","author":"Flaig","year":"2024","journal-title":"J Natl Compr Canc Netw"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13839","article-title":"Comparison of genomic characterization in upper tract urothelial carcinoma and urothelial carcinoma of the bladder","volume":"26","author":"Yang","year":"2021","journal-title":"Oncologist"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24135","article-title":"Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration","volume":"115","author":"Margulis","year":"2009","journal-title":"Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2018.01.015","article-title":"An analysis of staging and treatment trends for upper tract urothelial carcinoma in the National Cancer Database","volume":"16","author":"Browne","year":"2018","journal-title":"Clin Genitourin Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/aqaa105","article-title":"PD-L1 positivity associated with presence of tertiary lymphoid structures and high-stage disease in upper tract urothelial carcinoma","volume":"154","author":"Smith","year":"2020","journal-title":"Am J Clin Pathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02598-7","article-title":"Synergistic induction of tertiary lymphoid structures by chemoimmunotherapy in bladder cancer","volume":"130","author":"Zhang","year":"2024","journal-title":"Br J Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1824893\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:04:01Z","timestamp":1780898641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1824893\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2026.1824893"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1824893","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]},"article-number":"1824893"}}