Introduction
Tumors
TUMORS, SOLID TUMORS
Tumors employ a range of mechanisms to evade immune-mediated clearance (By virtue of a range of nonclinical evidence, costimulatory receptors have garnered significant interest as therapeutic targets, each harboring considerations for therapeutic utility (Feladilimab, a novel, humanized, clinical-stage anti-ICOS IgG4 mAb, is the first ICOS agonist mAb to be tested in first-in-human clinical trials; it was chosen for its selective binding to the ICOS receptor, which leads to stimulation of the ICOS signaling pathway and subsequent T-cell activation. This particular IgG4 isotype contains two amino acid substitutions (IgG4-PE; refs. Here, we discuss the expression and prognostic value of ICOS in solid tumors, outline the functional effects of ICOS agonism, and establish the unique mechanistic profile of feladilimab and its antitumor potential alone and in combination with PD-1 blockade in nonclinical models. We also report three patient case studies from an open-label, phase I clinical trial (INDUCE-1; NCT02723955; primary analyses not yet conducted). This study is designed to evaluate the safety and tolerability of feladilimab as monotherapy and in combination with the PD-1 inhibitor pembrolizumab in patients with advanced solid tumors; with an additional aim to identify the recommended phase II dose. Together, these data provide a spectrum of investigation for targeting ICOS (from nonclinical to clinical), supporting the therapeutic concept of antibody-based ICOS co-stimulation. However, more widespread clinical investigations are needed to optimize the selection of patient populations as well as the optimal dose and schedule, which are a challenge for agonist antibodies for ICOS-based therapeutic approaches (