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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-03-26 DOI:10.1016/j.xcrm.2025.102041

Ruth Plummer, Mikael H Sodergren, Rose Hodgson, Bríd M Ryan, Nina Raulf, Joanna P Nicholls, Vikash Reebye, Jon Voutila, Laura Sinigaglia, Tim Meyer, David J Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Thomas R Jeffrey Evans, Jeffrey Yachnin, Cheng E Chee, Daneng Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Madhava Pai, Duncan Spalding, Thomas Talbot, Marcus S Noel, Bridget Keenan, Devalingam Mahalingam, Min-Sun Song, Mélanie Grosso, Denis Arnaud, Aurelie Auguste, Dimitris Zacharoulis, Jan Storkholm, Iain McNeish, Robert Habib, John J Rossi, Nagy A Habib

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引用次数: 0

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).

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.