Tumor-targeted 4-1BB costimulation enhances immune activation and clinical activity of a CEA-directed T-cell engager in microsatellite-stable colorectal cancer

Cibisatamab is a carcinoembryonic antigen (CEA)–directed T-cell engaging bispecific antibody that has shown evidence of antitumor activity as a single agent in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) (ClinicalTrials.gov identifier: NCT02324257). Effective T-cell activation requires coordinated signaling through the TCR–CD3 complex and costimulatory pathways, including 4-1BB, which is induced following antigen recognition. We evaluated the combination of cibisatamab with escalating doses of FAP-4-1BBL, a fibroblast activation protein (FAP)–targeted 4-1BB agonist, in an open-label phase 1b study (BP42675; ClinicalTrials.gov identifier: NCT04826003) in patients with MSS mCRC who had progressed after at least two prior lines of therapy. The combination demonstrated a manageable safety profile and induced robust immune activation, characterized by sustained increases in circulating interferon-γ (IFNγ), soluble CD25 (sCD25), and proliferating/ activated CD8⁺ T-cell subsets, together with expansion of memory compartments. Compared with cibisatamab monotherapy, the combination resulted in greater and more durable induction of IFNγ and sCD25 without any exacerbation of cytokine-release–related toxicity. Treatment was associated with numerically higher overall response and disease control rates than previously reported for cibisatamab alone, with an overall response rate of 17.6% (9/51) and a disease control rate of 50.9% (26/51) across dose levels and schedules. Reductions in serum CEA, early decreases in circulating tumor DNA, and increased soluble CD137 were associated with clinical benefit. Paired tumor biopsies showed greater increases of intratumoral CD8⁺ and CD8⁺Ki67⁺ T-cell infiltration relative to cibisatamab monotherapy. Together, these findings support tumor-localized 4-1BB costimulation as a strategy to enhance the biological and clinical activity of T-cell engagers in MSS mCRC and other non-inflamed solid tumors.