The inducible T-cell co-stimulator (ICOS, CD278) represents an appealing yet complex target within the CD28 immunoglobulin receptor superfamily. Unlike constitutively expressed co-stimulatory molecules, ICOS is minimally present on naïve T cells and is upregulated following T-cell receptor engagement. This inducible expression pattern, and its crosstalk with other co-stimulatory pathways such as OX40, 4-1BB, CD40, and CD28, position ICOS as a promising candidate for immune agonism. The phase I INDUCE-1 study of the ICOS agonist feladilimab (GSK3359609) employed a pharmacodynamically guided design that prioritized biological activity over toxicity thresholds. Although feladilimab demonstrated favorable safety and robust receptor occupancy, clinical responses were limited—echoing similar experiences with vopratelimab (JTX-2011) and other ICOS agonists. These outcomes highlight that effective ICOS modulation depends not only on receptor engagement but also on spatial and temporal regulation of effector versus regulatory T-cell responses. Future ICOS-directed strategies, whether agonistic or antagonistic, monoclonal or bispecific, will require rational combination approaches and biomarker-driven patient selection to fully harness this pathway’s therapeutic potential.
Habibzadeh et al. (Thu,) studied this question.