Evolution of the tumor immune landscape during treatment with tebentafusp, a T cell receptor-CD3 bispecific Journal Article
| Authors: | Sacco, J. J.; Kirk, P.; Leach, E.; Shoushtari, A. N.; Carvajal, R. D.; Britton-Rivet, C.; Khakoo, S.; Collins, L.; de la Cruz-Merino, L.; Eroglu, Z.; Ikeguchi, A. P.; Nathan, P.; Hamid, O.; Butler, M. O.; Stanhope, S.; Ranade, K.; Sato, T. |
| Article Title: | Evolution of the tumor immune landscape during treatment with tebentafusp, a T cell receptor-CD3 bispecific |
| Abstract: | Metastatic uveal melanoma is an aggressive disease with poor outcome, which is refractory to immune checkpoint inhibitors. A T cell receptor (TCR)-based CD3 bispecific, tebentafusp, delivers clinical benefit in patients with metastatic uveal melanoma. Understanding the molecular basis for the anti-tumor activity of tebentafusp in an indication where checkpoint inhibitors are ineffective could aid in identification of other solid tumor indications where CD3 bispecifics may serve an unmet need. By analyzing tumor biopsies taken prior to treatment, early on-treatment, and at progression (NCT02570308), using RNA sequencing (RNA-seq) and immunohistochemistry (IHC), we show that expression of interferon-related genes in the tumor prior to treatment is associated with improved overall survival and tumor reduction on tebentafusp, that T cell recruitment occurs even in tumors with a low baseline level of T cell infiltration, and that durability of changes induced in the tumor microenvironment is key for survival duration. © 2025 The Authors |
| Keywords: | immunohistochemistry; human tissue; protein expression; human cell; phenotype; gene expression; cell infiltration; evolution; tumor biopsy; caspase 3; antineoplastic activity; cytotoxicity; uvomorulin; immune response; immunotherapy; gamma interferon; upregulation; liver cell; cutaneous melanoma; programmed death 1 ligand 1; cxcl9 chemokine; gp100; tumor microenvironment; tumor immunology; uveal melanoma; immune checkpoint inhibitor; high throughput sequencing; suppressor of cytokine signaling 1; human; article; bispecific; rna sequencing; whole exome sequencing; gene set enrichment analysis; tumor mutational burden; tebentafusp; t cell engager |
| Journal Title: | Cell Reports Medicine |
| Volume: | 6 |
| Issue: | 4 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2025-04-15 |
| Start Page: | 102076 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2025.102076 |
| PROVIDER: | scopus |
| PMCID: | PMC12047528 |
| PUBMED: | 40239619 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
