Anti-TNFR2 antibody BI-1808 induces tumor regression and antitumor T cell immunity through T reg and myeloid cell modulation in patients with solid tumors

Purpose: To clinically evaluate the safety, pharmacodynamic biomarkers, and efficacy of BI-1808, a first-in-class ligand-blocking, Fcγ receptor-engaging anti-TNFR2 antibody, as a novel immunotherapy approach to enhance antitumor immunity in solid cancer patients. Experimental Design: Preclinical modeling in syngeneic tumor models was used to assess the relationship between dose, pharmacokinetics, receptor occupancy, and efficacy, as well as pharmacodynamic biomarkers measured in peripheral blood and tumors. These findings informed dosing and analyses in a first-in-human phase 1 dose-escalation trial in patients with solid cancers. Results: BI-1808 was safe and well-tolerated, showed expected pharmacokinetics, and achieved full receptor occupancy throughout the three-week dosing interval. Tumor regression was observed in two patients, one with non-small cell lung cancer and one with gastrointestinal sarcoma. Stable disease was observed in 6 of 21 evaluable patients. Tumor regression was preceded by increases in circulating CX3CR1+CD8+ T cells and tumor-infiltrating CD8+ T cells, consistent with activation of antitumor immunity. Pharmacodynamic analyses were consistent with the preclinically characterized mechanism of action, including dose-dependent reduction of regulatory T cells, monocyte activation, and serum cytokines indicating myeloid reprogramming, tertiary lymphoid structure formation, and CD8+ T-cell activation. Conclusions: These early clinical findings support further development of ligand-blocking, Fcγ receptor-engaging anti-TNFR2 antibodies as a safe and mechanistically distinct cancer immunotherapy strategy. The excellent safety profile of BI-1808 makes it well-suited for combination with other immunotherapies, targeted agents, chemotherapeutics, cell therapies, and ADCs.