Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts Using a Humanized Anti-Fibroblast Activation Protein Antibody

Abstract Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAF), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized mAbs, specifically sibrotuzumab, which is an antihuman fibroblast activation protein (FAP) Ab and already being investigated in clinical trials as monotherapy. PDX models derived from patients with esophageal cancer were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line–derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared with control groups, all without inducing adverse events such as weight loss. Immunohistologic assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing sibrotuzumab as a promising therapeutic avenue for the clinical treatment of patients with esophageal cancer.