TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors
Many patients with cancer do not benefit from currently approved immune checkpoint inhibitors (ICIs), suggesting that additional immunomodulation of the immunosuppressive tumor microenvironment (TME) is required. MTL-CCAAT enhancer-binding protein alpha (CEBPA) specifically upregulates the expression of the master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumors that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with the combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune-desert toward a more immune-inflamed TME. Patients with disease stabilization demonstrate reductions in immunosuppressive myeloid cells post treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335).
Authors
- David James Pinato (ORCID: https://orcid.org/0000-0002-3529-0103)
- Min-Sun Song (ORCID: https://orcid.org/0000-0003-0143-4313)
- Rose Hodgson (ORCID: https://orcid.org/0000-0002-9157-045X)
- Jeffrey Yachnin
- Devalingam Mahalingam (ORCID: https://orcid.org/0000-0002-2979-9894)
- Bridget P. Keenan (ORCID: https://orcid.org/0000-0001-6075-489X)
- Anthony B. El-Khoueiry (ORCID: https://orcid.org/0000-0002-9053-3841)
- Bristi Basu (ORCID: https://orcid.org/0000-0002-3562-2868)
- Laura Sinigaglia
- Bríd M. Ryan (ORCID: https://orcid.org/0000-0003-0038-131X)
- Jon Voutila (ORCID: https://orcid.org/0000-0001-7193-2110)
- Mélanie Grosso
- Daneng Li (ORCID: https://orcid.org/0000-0001-5330-7522)
- Dimitris Zacharoulis (ORCID: https://orcid.org/0000-0003-0107-3976)
- Cheng Ean Chee (ORCID: https://orcid.org/0000-0003-2385-7712)
- John J. Rossi (ORCID: https://orcid.org/0000-0003-1238-9335)
- Ruth Plummer (ORCID: https://orcid.org/0000-0003-0107-1444)
- Nina Raulf
- Nagy Habib (ORCID: https://orcid.org/0000-0003-4920-4154)
- Vikash Reebye (ORCID: https://orcid.org/0000-0003-0811-5323)
- Marcus Smith Noel (ORCID: https://orcid.org/0000-0002-3658-6950)
- Tim Meyer (ORCID: https://orcid.org/0000-0003-0782-8647)
- Mikael H. Sodergren (ORCID: https://orcid.org/0000-0002-7141-3924)
- Sarah P. Blagden (ORCID: https://orcid.org/0000-0001-8783-3491)
- Natalie Cook (ORCID: https://orcid.org/0000-0003-2606-1082)
- Thomas R. Talbot (ORCID: https://orcid.org/0000-0002-6139-212X)
- Duncan Spalding (ORCID: https://orcid.org/0000-0001-5066-054X)
- Aurélie Auguste (ORCID: https://orcid.org/0000-0001-5115-0218)
- Maria Diab (ORCID: https://orcid.org/0000-0002-4809-9535)
- Iain A. McNeish (ORCID: https://orcid.org/0000-0002-9387-7586)
- Debashis Sarker (ORCID: https://orcid.org/0000-0003-4814-8429)
- Kai‐Wen Huang (ORCID: https://orcid.org/0000-0001-6375-8714)
- Madhava Pai (ORCID: https://orcid.org/0000-0003-1760-9632)
- T.R. Jeff Evans
- Joanna P. Nicholls
- Robert Habib
- Denis Arnaud
- Jan Henrik Storkholm
Institutions
- University of Southern California (US)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Guy's Hospital (GB)
- Karolinska University Hospital (SE)
- Emory University (US)
- King's College - North Carolina (US)
- University of California, San Francisco (US)
- Georgetown University (US)
- Beatson West of Scotland Cancer Centre (GB)
- Churchill Hospital (GB)
- Cancer Research UK (GB)
- Freeman Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- MedStar Georgetown University Hospital (US)
- National University Cancer Institute, Singapore (SG)
- University Hospital of Larissa (GR)
- City of Hope (US)
- CTI BioPharma (United Kingdom) (GB)
- USC Norris Comprehensive Cancer Center (US)
- Veracyte (United States) (US)
- National Taiwan University Hospital (TW)
- The Christie NHS Foundation Trust (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- King's College Hospital (GB)
- Beckman Research Institute
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102041
- Citations
- 9
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 9.41
Funders
- Falk Foundation
- Amgen
- Bristol-Myers Squibb
- AstraZeneca
- GlaxoSmithKline
- F. Hoffmann-La Roche
- Boston Scientific Corporation
- Regeneron Pharmaceuticals
- Astex Pharmaceuticals
- BeiGene
- Incyte
- Tarveda Therapeutics
- NuCana
- NGM Biopharmaceuticals
- Actuate Therapeutics
- Moderna
- Cancer Research UK
- National Institute for Health and Care Research
- Imperial College London
- University College London
- Newcastle University
- University of Glasgow
- Eisai
- Servier
- Ipsen
- Sirtex Medical
- Genentech
- Menzies Centre for Australian Studies, King's College London, University of London