Abstract CT105: FAP-targeted 4-1BBL trimeric costimulation amplifies T-cell activation and antitumor efficacy of a CEA-directed T-cell engager in MSS colorectal cancer

Abstract Background: Cibisatamab is a carcinoembryonic antigen (CEA)-targeting T-cell bispecific antibody (TCB) that has demonstrated T-cell activation and antitumor activity as a single agent in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) (Segal et al., 2024; NCT02324257). Full T-cell activation, however, requires integrated signaling through the TCR-CD3 complex and costimulatory pathways such as those mediated by the 4-1BB receptor, expressed on antigen-primed T cells. Methods: We evaluated the combination of cibisatamab with escalating doses of FAP-4-1BBL, a fibroblast activation protein (FAP)-dependent 4-1BB agonist, in an open-label Phase 1b study (BP42675; NCT04826003) in patients with MSS mCRC who had progressed after ≥2 prior lines of therapy. Results: The combination of cibisatamab and FAP-4-1BBL demonstrated a manageable safety profile. Building on initial findings, the combination induced robust peripheral immune activation, characterized by elevated inflammatory cytokines, proliferating/activated CD8⁺ T cells, and expansion of effector memory (CD8⁺CD45RA⁻CD197⁻) and terminally differentiated effector TEMRA (CD8⁺CD45RA⁺CD197⁻) subsets, including their PD-1⁺ activated counterparts, in peripheral blood. These systemic changes were accompanied by enhanced intratumoral CD8⁺/CD8⁺Ki67⁺ infiltration. Compared with cibisatamab alone, the combination elicited stronger and more persistent pharmacodynamic effects. Clinically, the combination achieved encouraging efficacy, with an overall response rate (ORR) of 17.6% (9/51) and a disease control rate (DCR) of 50.9% (26/51) across all FAP-4-1BBL dose levels and dosing interval cohorts—numerically higher than observed with cibisatamab alone. Notably, in the highest FAP-4-1BBL dose groups of the QW regimen tested (90 mg and 130 mg) 4 out of 11 patients achieved a PR (36.4%). Decreases in plasma sCEA levels, early reductions in circulating tumor DNA (ctDNA), and increases in soluble CD137 (sCD137) correlated with improved clinical outcomes. Paired tumor biopsies showed enhanced CD8⁺ and CD8⁺Ki67⁺ T-cell infiltration in the combination arm compared with cibisatamab monotherapy. Conclusions: These data suggest that FAP-targeted 4-1BB costimulation can potentiate the antitumor activity of CEA-directed T-cell bispecific antibodies. The results support further development of tumor-localized 4-1BB agonists in combination with T-cell-engaging therapies for MSS mCRC and other non-inflamed (“cold”) tumors. Citation Format: Ignacio Melero, Tamara Tanos, Emiliano Calvo Aller, Victor Moreno, Camilla Qvortrup, Marloes van Dongen, Josep Tabernero, Seung-Hoon Beom, Fiona Thistlethwaite, Maria del Carmen Riesco-Martínez, Maria Martinez Garcia, Victoria Woodcock, Tae Won Kim, Pablo Umaña, Christine McIntyre, Lining Chen, Christian Heichinger, Heather Hinton, Tulun Saylan, Iakov I. Davidov, Chiahuey Ooi, Ernesto Guarín, Axel Boehnke. FAP-targeted 4-1BBL trimeric costimulation amplifies T-cell activation and antitumor efficacy of a CEA-directed T-cell engager in MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT105.