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Researchers describe preclinical‑to‑clinical pipeline tying entinostat and checkpoint blockade to myeloid modulation and spatial biomarkers
Summary
A presenter reviewed preclinical evidence that class‑I HDAC inhibition (entinostat) reduces myeloid‑mediated suppression and, combined with dual checkpoint blockade, produced signals in a phase 1b trial; mathematical models and spatial single‑cell analyses helped identify macrophage–T cell ICAM1 interactions that correlate with response.
Dr. Eventhia Rosals Torres summarized efforts to translate a systems‑level discovery into early clinical testing. She described preclinical mouse work showing that entinostat (a class‑I histone deacetylase inhibitor) abates the suppressive activity of MDSCs and macrophages, and that combining entinostat with anti‑CTLA‑4 and anti‑PD‑1 produced enhanced anti‑tumor activity in models of triple negative and HER2+ breast cancer.
Those preclinical signals motivated a phase 1 study in advanced solid tumors and a small expansion cohort in advanced breast cancer. In the multi‑tumor phase 1 study the presenter reported a 16% overall response in treated patients; in a small breast cancer expansion the speaker reported a 40% objective response rate in triple negative cases and 10% in hormone‑receptor positive patients (numbers described as preliminary and from a small cohort). The presenter emphasized the limited sample sizes and called the results hypothesis‑generating rather than definitive.
To better understand mechanisms, her group used mathematical modeling and single‑cell and spatial analyses. Preclinical single‑cell RNA‑seq and ligand–receptor pairing analysis implicated macrophage–T cell chemokine and ICAM1‑related interactions as mediators of the antitumor response. Functional macrophage blockade of ICAM1 in ex vivo assays increased T‑cell proliferation, but the presenter said blocking ICAM1 alone was insufficient to reproduce the full effect of entinostat in models, arguing that entinostat has pleiotropic actions across multiple cell types.
Spatial imaging cytometry of patient samples supported a model in which responder biopsies showed changing proximity between CD8+ T cells and macrophages over treatment time—consistent with reduced ICAM1‑mediated retention in some responding cases. The presenter framed the work as an example of an iterative translational pipeline: preclinical discovery, early clinical testing, single‑cell spatial measurement and mathematical modeling to identify candidate mechanisms and refine hypotheses for subsequent trials.
