顶膀含铂化疗和免疫检查点阻断可能与持久的转移性膀胱癌患者中的疾病控制相关。然而，这一现象的机制基础仍不清楚。抗肿瘤免疫可能是这些特异性反应者的基础。在一项评估顺序方案的II期临床试验中，对转移性膀胱癌用吉西他滨和顶膀含铂联合培毕单抗进行治疗，共36名患者中有4名达到持久无病存活（DDFTFS）并在入组后5年仍保持缓解。我们试图确定与这些患者的功能性治愈相关的基因组和免疫学机制。对术前可获得的肿瘤组织进行了全外显子测序。采用一种新的流程进行新抗原的预测和排序。对于有可用生物样本的患者的子集，在基线、化疗后以及化疗和培毕单抗时间点，利用自体抗原递呈细胞培养外周血CD4+和CD8+ T细胞进行新抗原特异性T细胞活性测试。同时还评估了每个时间点的血清蛋白分析的多重检测。血清蛋白组学分析显示，在术前，DDFTFS患者表现出免疫激活的表型，TH1适应性免疫、共刺激分子和免疫检查点标记物升高。经过联合顶膀含铂化疗和培毕单抗治疗后，DDFTFS患者再次显示出适应性免疫标志物的富集，以及T细胞细胞毒性。CD27在所有时间点上都在DDFTFS患者中独特富集。在任何一个患者的基线或化疗后两个疗程中都没有检测到新抗原反应性。经过顶膀含铂化疗和培毕单抗治疗后，与零比五的非-DDFTFS患者相比，两个DDFTFS患者中均检测到CD4+和CD8+新抗原特异性T细胞活性。抗肿瘤免疫可能是转移性膀胱癌患者通过顶膀含铂化疗和免疫检查点阻断实现功能性治愈的基础。探索DDFTFS的机制基础可能有助于确定生物标志物、治疗组合和最佳治疗顺序，以扩大这一终极目标的适用范围。© 作者（或其雇主）2023年。使用CC BY-NC许可。不允许商业再使用。由BMJ出版。

Cisplatin-based chemotherapy has been associated with durable disease control in a small subset of patients with metastatic urothelial cancer. However, the mechanistic basis for this phenomenon has remained elusive. Antitumor immunity may underlie these exceptional responders. In a phase II trial evaluating a phased schedule of gemcitabine and cisplatin followed by gemcitabine and cisplatin with ipilimumab for metastatic urothelial cancer, 4 of 36 patients achieved durable disease-free treatment-free survival (DDFTFS) and remain in remission over 5 years after enrolment on the study. We sought to identify the genomic and immunological mechanisms associated with functional cures of such patients. Whole exome sequencing was performed on pretreatment archival tumor tissue. Neoantigen prediction and ranking were performed using a novel pipeline. For a subset of patients with available biospecimens, selected peptides were tested for neoantigen-specific T cell reactivity in peripheral blood CD4+ and CD8+ T cells cultured with autologous antigen-presenting cells at baseline, postchemotherapy, and postchemotherapy and ipilimumab timepoints. Multiplex assays of serum protein analytes were also assessed at each time point. Serum proteomic analysis revealed that pretreatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in TH1 adaptive immunity, costimulatory molecules, and immune checkpoint markers. After combination cisplatin-based chemotherapy and ipilimumab treatment, DDFTFS patients again displayed enrichment for markers of adaptive immunity, as well as T cell cytotoxicity. CD27 was uniquely enriched in DDFTFS patients at all timepoints. Neoantigen reactivity was not detected in any patient at baseline or post two cycles of chemotherapy. Both CD4+ and CD8+ neoantigen-specific T cell reactivity was detected in two of two DDFTFS patients in comparison to zero of five non-DDFTFS patients after combination cisplatin-based chemotherapy and ipilimumab treatment. Antitumor immunity may underlie functional cures achieved in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy and immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of biomarkers, therapeutic components, and optimal treatment sequences necessary to extend this ultimate goal to a larger subset of patients.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.