Evolution of the tumor immune landscape during treatment with tebentafusp, a T cell receptor-CD3 bispecific
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.
Authors
- Marcus O. Butler (ORCID: https://orcid.org/0000-0002-9840-7057)
- Luis de la Cruz‐Merino (ORCID: https://orcid.org/0000-0002-5333-0535)
- Laura C. Collins (ORCID: https://orcid.org/0000-0001-6751-4792)
- Zeynep Eroglu (ORCID: https://orcid.org/0000-0002-2307-7030)
- Omid Hamid (ORCID: https://orcid.org/0000-0002-8238-4655)
- Alexander Noor Shoushtari (ORCID: https://orcid.org/0000-0002-8065-4412)
- Emma Leach (ORCID: https://orcid.org/0000-0002-2831-092X)
- Takami Sato (ORCID: https://orcid.org/0000-0003-2221-0415)
- Sarah Stanhope (ORCID: https://orcid.org/0000-0002-7660-3591)
- Joseph J. Sacco (ORCID: https://orcid.org/0000-0003-2591-9796)
- Paul Nathan (ORCID: https://orcid.org/0000-0002-2327-3250)
- Richard D. Carvajal (ORCID: https://orcid.org/0000-0002-3796-1118)
- Camille Britton-Rivet
- Alexandra P. Ikeguchi (ORCID: https://orcid.org/0000-0002-4448-9755)
- Sophie Khakoo
- Peter Kirk
- Koustubh Ranade
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cornell University (US)
- Cold Spring Harbor Laboratory (US)
- Mount Vernon Hospital (GB)
- Princess Margaret Cancer Centre (CA)
- Clatterbridge Cancer Centre NHS Foundation Trust (GB)
- Moffitt Cancer Center (US)
- Hospital Universitario Virgen Macarena (ES)
- Immunocore (United States) (US)
- Immunocore (United Kingdom) (GB)
- Sidney Kimmel Cancer Center (US)
- Mount Vernon Cancer Centre (GB)
- University College London (GB)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102076
- Citations
- 6
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 6.27