Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment

作者：Brenda O’Connell, Charley J. Hubbard, Nora Zizlsperger, Donna M. Fitzgerald, Jeffrey L. Kutok, Judith A. Varner, Robert Ilaria, Melody Cobleigh, Dejan Juric, K.H. Tkaczuk, Anthony Elias, Arielle Lee, Shaker R. Dakhil, Erika Hamilton, Hatem Soliman, Stéphane Peluso · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2024-009160 · 被引用次数：64 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICI) in combination with chemotherapies have demonstrated promising clinical benefit in metastatic TNBC (mTNBC) but there is still an unmet need, particularly for patients with PD-L1 negative tumors. Mechanisms of resistance to ICIs in mTNBC include the presence of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Eganelisib is a potent and selective, small molecule PI3K-γ inhibitor that was shown in preclinical studies to reshape the TME by reducing myeloid cell recruitment to tumors and reprogramming TAMs from an immune-suppressive to an immune-activating phenotype and enhancing activity of ICIs. These studies provided rationale for the clinical evaluation of eganelisib in combination with the anti-PD-L1 atezolizumab and nab-paclitaxel in firstline mTNBC in the phase 2 clinical trial MAcrophage Reprogramming in Immuno-Oncology-3 (MARIO-3, NCT03961698). We present here for the first time, in-depth translational analyses from the MARIO-3 study and supplemental data from eganelisib monotherapy Ph1/b study in solid tumors (MARIO-1, NCT02637531). METHODS: Paired pre-treatment and post-treatment tumor biopsies were analyzed for immunophenotyping by multiplex immunofluorescen...