TGF-β, the Architect of Disaster

Jul 10, 2024

The most heavily fortified and militarized border in the world isn’t the one between North and South Korea, all appearances to the contrary. That distinction belongs instead to the border between tumors and their surrounding tissues.

Chiefly responsible for the impregnable state of this border is the cytokine, transforming growth factor-beta (TGF-β). With the help of TGF-β and other cytokines, many tumors effectively barricade themselves behind 1) thick, rigid walls of scar tissue, 2) a moat-like, a nearly impassable vasculature, 3) an immunosuppressive shield of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages, and 4) an oppressive miasma of poorly oxygenated air that in the aggregate protects these tumors against the predations of the host immune system, and makes them partially or completely resistant to chemotherapy, radiation, targeted therapies, and immune checkpoint inhibitors (ICIs).

The EpicentRx strategy is to target the tumor, and its chief architect, the profibrotic, proangiogenic, prohypoxic, immunosuppressive cytokine, TGF-β, with lead EpicentRx therapy, AdAPT-001. Designed by EpicentRx CEO, Dr. Tony Reid, to only lyse tumor cells, AdAPT-001 also carries and expresses a TGF-β trap that binds to and eliminates TGF-β.

A minority of patients respond to ICIs up front, but most do not, and many ICI responders eventually experience tumor progression. From ongoing clinical trial data at the MD Anderson Cancer Center with PI, Dr., Anthony P. Conley, and the Cleveland Clinic with PI, Dr. Lucy B. Kennedy, AdAPT-001 reverses established checkpoint inhibitor resistance in hard-to-treat tumors like sarcomas and triple negative breast cancer through several likely mechanisms: it combats T cell exhaustion, reprograms the tumor microenvironment, increases the availability of tumor neo-antigens, and silences the transcription of key protumor genes like myc and survivin.

If AdAPT-001 were to come with a tagline, it might read, “kill the Architect, save the Patient.”