Journal Article

Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer

Uzilov, Andrew, Bhardwaj, Nina, Galsky, Matthew D, Sebra, Robert, Halperin, Rebecca, Imai, Naoko, Kim-Schulze, Seunghee, Pal, Sumanta K, Wang, Huan, Hahn, Noah M, Gnjatic, Sacha, Anker, Jonathan, Saito, Takuro, Patel, Manishkumar, Qi, Jingjing, Eikawa, Shingo, Xie, Hui

2023

Overview

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 T H 1 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.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Bladder cancer / Cancer / Carcinoma, Transitional Cell - drug therapy / CD8-Positive T-Lymphocytes / Chemokines / Chemotherapy / Cisplatin - therapeutic use / Clinical/Translational Cancer Immunotherapy / Disease control / Disease-Free Survival / Flow cytometry / Humans / Immunity (Disease) / Immunotherapy / Ipilimumab - therapeutic use / Lymphocytes / Metastasis / Monoclonal antibodies / Patients / Peptides / Proteomics / Software