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Unlike constitutively expressed co-stimulatory molecules, ICOS is minimally present on na\u00efve 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\u2014echoing 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\u2019s therapeutic potential.<\/jats:p>","DOI":"10.1136\/jitc-2025-013991","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T14:50:20Z","timestamp":1769698220000},"page":"e013991","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Advancing ICOS agonism in solid tumors: lessons from INDUCE-1"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2086-0425","authenticated-orcid":false,"given":"Parham","family":"Habibzadeh","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7846-8055","authenticated-orcid":false,"given":"Diwakar","family":"Davar","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"2026012906501546000_14.1.e013991.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132706"},{"key":"2026012906501546000_14.1.e013991.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.006"},{"key":"2026012906501546000_14.1.e013991.3","doi-asserted-by":"crossref","unstructured":"Sun Q , Hong Z , Zhang C , et al . 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Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1\/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2). J Immunother Cancer 2024;12. doi:10.1136\/jitc-2024-009474","DOI":"10.1136\/jitc-2024-009474"},{"key":"2026012906501546000_14.1.e013991.8","doi-asserted-by":"publisher","DOI":"10.1038\/16717"},{"key":"2026012906501546000_14.1.e013991.9","doi-asserted-by":"crossref","unstructured":"Schepp J , Chou J , Skrabl-Baumgartner A , et al . 14\u2009Years after Discovery: Clinical Follow-up on 15 Patients with Inducible Co-Stimulator Deficiency. 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