The FAP × CD3 bispecific antibody OMTX305 induces T cell-mediated antitumor effects in patient-derived ex vivo models...

Within solid tumors, stromal barriers and immune exclusion limit the success of immunotherapies. Thus, novel therapeutic approaches are required to remodel the tumor-supportive microenvironment and enhance therapeutic responses. We developed a bispecific, trivalent Fab-eIg T cell engager (OMTX305) targeting fibroblast activation protein (FAP), a marker of tumor-promoting cancer-associated fibroblasts. The translational potential of OMTX305 was investigated in 2D and 3D patient-derived preclinical models, with a focus on precision-cut tumor slices (PCTSs) of lung and ovarian cancer cocultured with autologous PBMCs. By combining spatial biology with cytokine and transcriptomic analysis, we show that OMTX305 treatment eliminated FAP-expressing fibroblasts, induced interferon responses and extracellular matrix remodeling, ultimately triggering bystander killing of adjacent tumor cells. Distinct immune phenotypes and PD-L1 expression patterns appeared to be associated with differential treatment responses, suggesting their potential as biomarkers for patient stratification. Our findings highlight the clinical potential of targeting stromal elements as a cancer therapy and establish PCTS as a powerful preclinical platform for personalized immunotherapy assessment.