Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer

• DOI: 10.1084/jem.20240152
• Publication Date: 2024-08-27T15:07:41Z
• Authors: Apostolia M. Tsim...; Farah A. Alayli; Kwame Okrah; Alexandra Drakaki; Danny N. Khalil; Shivaani Kummar; Saad A. Khan; F. Stephen Hodi; David Y. Oh; Christopher R. Ca...; Shikha Gautam; Stefanie L. Meier; Meelad Amouzgar; Shannon M. Pfeiffer; Robin Kageyama; EnJun Yang; Marko Spasic; Michael T. Tetzlaff; Wai Chin Foo; Travis J. Hollmann; Yanyun Li; Matthew Adamow; Phillip Wong; Jonni S. Moore; Sharlene Velichko; Richard O. Chen; Dinesh Kumar; Samantha Bucktrout; Ramy Ibrahim; Ute Dugan; Lisa Salvador; Vanessa M. Hubbar...; Jill O’Donnell-To...; Sandra Santulli-M...; Lisa H. Butterfield; Diane M. Da Silva; Justin Fairchild; Theresa M. LaVallee; Lacey J. Padrón; Padmanee Sharma
• Keywords: Adult; Male; 0301 basic medicine; Medical Sciences; Bioinformatics; Drug Resistance; 610; CD8-Positive T-Lymphocytes; Article; Biomedical Informatics; 03 medical and health sciences; Neoplasms; Medical Specialties; Medicine and Health Sciences; Tumor Microenvironment; Humans; Neoplasm Metastasis; Immune Checkpoint Inhibitors; Aged; Middle Aged; Ipilimumab; Nivolumab; Oncology; Drug Resistance, Neoplasm; Neoplasm; Female

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.