The C/EBPβ antagonist peptide Lucicebtide (ST101) induces macrophage polarization toward a pro-inflammatory phenotype and enhances anti-tumor immune responses

Claudio Scuoppo Ricardo Ramirez Siok Leong Mark Koester Zachary Mattes Karen Mendelson Julia Diehl Franco Abbate Erin Gallagher Lila Ghamsari Abi Vainstein-Haras Gene Merutka Barry Kappel Jim Rotolo ^*

• Sapience Therapeutics, Tarrytown, United States

Immune-checkpoint inhibitors (ICIs) have shown unprecedented success in a subset of immunogenic tumors, however a host of patients with advanced solid tumors fail to respond well or at all to immunotherapy. Refractory tumors commonly display a tumor microenvironment (TME) rich in immunosuppressive macrophages (M2-like) that suppress adaptive immunity and promote tumor progression. The ability to reprogram macrophages in the TME to an immune-active state thus represents great promise to improve responses to ICIs. Lucicebtide (previously referred to as ST101) is a peptide antagonist of the transcription factor C/EBPβ, a key activator of the transcriptional program in immunosuppressive macrophages. Here we show that Lucicebtide exposure reprograms human M2-like macrophages to the pro-inflammatory M1-like phenotype, restores cytotoxic T cell activation in immunosuppressed co-culture assays in vitro, and further increases T-cell activity in M1-like/T cell co-cultures. In immunocompetent, macrophage-rich triple-negative breast and colorectal cancer models, Lucicebtide induces repolarization of tumor-associated macrophages (TAMs) to an M1-like phenotype and suppresses tumor growth. Lucicebtide synergizes with anti-PD-1 therapy and overcomes resistance to checkpoint inhibition in anti-PD-1-refractory tumors, but in vivo responses are impaired by systemic macrophage depletion, indicating that macrophage reprogramming is integral to Lucicebtide activity. These results identify Lucicebtide as a novel immunomodulator that reprograms immunosuppressive macrophage populations to enhance anti-tumor activity and suggests its utility for combination strategies in cancers with poor response to ICIs.