CTNI-68. C/EBPβ INHIBITION BY LUCICEBTIDE IN A WINDOW-OF-OPPORTUNITY SURGICAL TRIAL FOR GLIOBLASTOMA SUPPRESSES THE MESENCHYMAL PHENOTYPE AND PROMOTES AN IMMUNOSTIMULATORY TUMOR MICROENVIRONMENT

Abstract Glioblastoma (GBM) is a universally lethal brain malignancy with no cure. The tumor almost always recurs despite treatment. Recurrent GBM (rGBM) is enriched in a mesenchymal-like state, and the tumor microenvironment (TME) of rGBM is enriched in immune-suppressive tumor-associated myeloid cells (TAMs) with scarce T-cells. The resistance of mesenchymal GBM cells to standard chemotherapies and radiation, as well as the immune-suppressive TME in rGBM, continue to pose significant challenges to developing a cure. C/EBPβ is a master regulator of the mesenchymal GBM state and plays a central role in sustaining immunosuppressive TAMs. Lucicebtide (ST101) is a first-in-class peptide antagonist of C/EBPβ that has demonstrated anti-tumor activity and TAM reprogramming in preclinical models, making it a promising therapeutic candidate in GBM. Here, we present the results of tissue-based analysis from a window-of-opportunity surgical study that enrolled nine patients with rGBM and nine with newly diagnosed GBM. The patients received 2–4 weekly doses of Lucicebtide before surgery. Post-operatively, rGBM patients resumed Lucicebtide until progression, while newly diagnosed GBM patients received Lucicebtide combined with chemoradiation. The results showed that Lucicebtide was well tolerated as monotherapy and in combination with chemoradiation. Tissue-based analyses of a subset of patients using snRNAseq revealed that Lucicebtide dampened cell-type-specific C/EBPβ gene regulons. Using spatial transcriptomics from paired samples before and after treatment from six patients, we demonstrate the spatial patterns of C/EBPβ regulon activity in heterogeneous niches, and show evidence that Lucicebtide targets mesenchymal GBM in these niches. Importantly, C/EBPβ inhibition altered the infiltration patterns and phenotypes of TME T-cells, which exhibited increased transcriptional hallmarks of an effector CD8⁺ phenotype. This unique clinical trial demonstrates that Lucicebtide effectively engages its target in human GBM, leading to suppression of the mesenchymal GBM state and a reprogramming of the TME. These findings support further clinical development of Lucicebtide as a novel therapeutic approach for GBM.