Faculty, Staff and Student Publications
Publication Date
2-25-2025
Journal
Journal of Immunotherapy of Cancer
Abstract
Background: Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.
Methods and results: Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease < 6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate < 0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1).
Conclusions: Overall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.
Keywords
Humans, Female, Nivolumab, Anilides, Endometrial Neoplasms, Pyridines, Biomarkers, Tumor, Neoplasm Recurrence, Local, Antineoplastic Combined Chemotherapy Protocols, Middle Aged, Drug Resistance, Neoplasm, Aged, Immunotherapy, Biomarker, Next generation sequencing - NGS, Antibody, Immune Checkpoint Inhibitor
DOI
10.1136/jitc-2024-010541
PMID
40010771
PMCID
PMC11865721
PubMedCentral® Posted Date
2-25-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Immunotherapy Commons, Medical Genetics Commons, Oncology Commons