Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Cell reports. Medicine. 2024 Jan 17 [Epub ahead of print]

Matthew D Galsky, Xiangnan Guan, Deepali Rishipathak, Aaron S Rapaport, Hesham M Shehata, Romain Banchereau, Kobe Yuen, Eugene Varfolomeev, Ruozhen Hu, Chia-Jung Han, Haocheng Li, Yuxin Liang, Domagoj Vucic, Li Wang, Jun Zhu, Haocheng Yu, Rebecca H Herbst, Emma Hajaj, Evgeny Kiner, Aristotelis Bamias, Maria De Santis, Ian D Davis, José Ángel Arranz, Eiji Kikuchi, Sandrine Bernhard, Patrick Williams, Chooi Lee, Ira Mellman, Shomyseh Sanjabi, Robert Johnston, Peter C Black, Enrique Grande, Sanjeev Mariathasan

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: ., Genentech Inc., South San Francisco, CA 94080, USA., Hoffmann-La Roche Ltd, Mississauga, ON, Canada., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; GeneDx, Stamford, CT, USA., GeneDx, Stamford, CT, USA., Immunai, New York, NY, USA., National and Kapodistrian University of Athens, Athens, Greece., Department of Urology, Charité - Universitätsmedizin, Berlin, Germany; Department of Urology, Medical University of Vienna, Vienna, Austria., Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia., Gregorio Marañón General University Hospital, Madrid, Spain., St. Marianna University School of Medicine, Kawasaki, Japan., Roche Products Ltd, Welwyn Garden City, UK., Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., MD Anderson Cancer Center Madrid, Madrid, Spain., Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: .