Ad-SGE-DKK3 Gene Therapy Overcomes Resistance to Immune Checkpoint Blockade in Pleural Mesothelioma

Abstract Purpose: Immune checkpoint inhibitors (ICIs) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) in overcoming treatment resistance. Experimental Design: We performed preclinical studies to elucidate DKK3’s role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with objective response rate (ORR) as the primary outcome. Results: DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and reduced extracellular vesicle secretion and Colony Stimulating Factor 1 (CSF1). DKK3 sensitized the tumor-immune microenvironment to ICIs and enabled eradication of tumors by PD-1 blockade. In our trial, twelve patients received intratumoral Ad-SGE-DKK3 plus intravenous nivolumab. ORR was 16.6% and 41.7% had stable disease, for a 58.3% rate of durable clinical response (DCB). Median overall survival was 14.5 months, and median progression-free survival was 4.5 months. Grade 3 adverse events occurred in 41.7% of patients. Serial tumor biopsies and serum analyses revealed that DCB patients had increased tumor-infiltrating bulk and effector memory CD8 T cells, reduced circulating memory CD8 T cells, and sustained lower soluble mesothelin and CSF1 levels compared to progressors. Conclusions: Combination Ad-SGE-DKK3 plus nivolumab demonstrated a tolerable safety profile and potential efficacy in patients with chemotherapy-refractory epithelioid pleural mesothelioma. ClinicalTrials.gov identifier: NCT04013334.