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TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors

Plummer, R.
; 
Sodergren, M. H.
; 
Hodgson, R.
; 
Ryan, B. M.
; 
Raulf, N.
; 
Nicholls, J. P.
; 
Reebye, V.
; 
Voutila, J.
; 
Sinigaglia, L.
; 
Meyer, T.
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Abstract
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
Plummer, R.
Sodergren, M. H.
Hodgson, R.
Ryan, B. M.
Raulf, N.
Nicholls, J. P.
Reebye, V.
Voutila, J.
Sinigaglia, L.
Meyer, T.
Pinato, D. J.
Sarker, D.
Basu, B.
Blagden, S.
Cook, N.
Jeffrey Evans, T. R.
Yachnin, J.
Chee, C. E.
Li, D.
El-Khoueiry, A.
Diab, M.
Huang, K. W.
Pai, M.
Spalding, D.
Talbot, T.
Noel, M. S.
Keenan, B.
Mahalingam, D.
Song, M. S.
Grosso, M.
Arnaud, D.
Auguste, A.
Zacharoulis, D.
Storkholm, J.
McNeish, I.
Habib, R.
Rossi, J. J.
Habib, N. A.
Affiliation
The Northern Centre for Cancer Care, Freeman Hospital, NE7 7DN Newcastle, UK. Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK. MiNA Therapeutics Ltd, W12 0BZ London, UK. Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; MiNA Therapeutics Ltd, W12 0BZ London, UK. Research Department of Oncology, UCL Cancer Institute, University College London, WC1E 6DD London, UK. Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; Department of Translational Medicine (DIMET), Università Del Piemonte Orientale 'A. Avogadro', Novara, Italy. Department of Research Oncology, Guys Hospital, Kings College London, SE1 9RT London, UK. University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK. Department of Oncology, Oxford University, Churchill Hospital, OX3 7LE Oxford, UK. University of Manchester and The Christie NHS Foundation Trust, M20 4BX Manchester, UK. The Beatson West of Scotland Cancer Centre, University of Glasgow, G12 0YN Glasgow, UK. Centrum Kliniska Cancerstudier, Karolinska University Hospital, 17176 Stockholm, Sweden. National University Hospital, National University Cancer Institute Singapore, Singapore 11928, Singapore. Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Norris Comprehensive Cancer Centre, Keck Medicine, University of Southern California, Los Angeles, CA 90089, USA. Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. National Taiwan University Hospital, Taipei, Taiwan. Medstar Georgetown University Hospital, Washington, DC 20007, USA. University of California San Francisco, San Francisco, CA 94143, USA. Robert H Lurie Comprehensive Cancer Centre, Northwestern University, Chicago, IL 60611, USA. Beckman Research Institute, City of Hope, CA, USA. Veracyte, Marseilles, France. Department of General Surgery, University Hospital of Larissa, Larissa, Greece. Department of Surgery & Cancer, Imperial College London, W12 0NN London, UK; MiNA Therapeutics Ltd, W12 0BZ London, UK. Electronic address: nagy.habib@imperial.ac.uk.
Description
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2025
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All Christie Publications
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Plummer R, Sodergren MH, Hodgson R, Ryan BM, Raulf N, Nicholls JP, et al. TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors. Cell reports Medicine. 2025 Apr 15;6(4):102041. PubMed PMID: 40168999. Pubmed Central PMCID: PMC12047497. Epub 2025/04/02. eng.
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https://christie.openrepository.com/handle/10541/628197
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