TIMEPOINT, a phase 1 study combining MTL-CEBPA with pembrolizumab, supports the immunomodulatory effect of MTL-CEBPA in solid tumors
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 P. Blagden, Natalie Cook, T.R. Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Daneng Li, Anthony B. El-Khoueiry, Maria Diab, Kai‐Wen Huang, Madhava Pai, Duncan Spalding, Thomas R. Talbot, Marcus Smith Noel, Bridget Keenan, Devalingam Mahalingam, Min-Sun Song, Mélanie Grosso, Denis Arnaud, Aurélie Auguste, Dimitris Zacharoulis, Jan Henrik Storkholm, Iain A. McNeish, Robert Habib, John J. Rossi, Nagy Habib
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).