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

PURPOSE

Immune checkpoint inhibitors (ICI) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT signaling pathway inhibitor 3 (DKK3) in overcoming treatment resistance.

PATIENTS AND METHODS

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 the objective response rate 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 the colony-stimulating factor 1. DKK3 sensitized the tumor immune microenvironment to ICIs and enabled the eradication of tumors by PD-1 blockade. In our trial, 12 patients received intratumoral Ad-SGE-DKK3 plus intravenous nivolumab. The objective response rate was 16.6%, and 41.7% had stable disease, for a 58.3% rate of durable clinical response. The median overall survival was 14.5 months, and the 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 patients with durable clinical response had increased tumor-infiltrating bulk and effector memory CD8 T cells, reduced circulating memory CD8 T cells, and sustained lower soluble mesothelin and the colony-stimulating factor 1 levels compared with progressors.

CONCLUSIONS

Combination Ad-SGE-DKK3 plus nivolumab demonstrated a tolerable safety profile and potential efficacy in patients with chemotherapy-refractory epithelioid pleural mesothelioma.