Language

English

Publication Date

7-1-2025

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-24-4024

PMID

40208070

PMCID

PMC12237568

PubMedCentral® Posted Date

1-1-2026

Abstract

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.

Keywords

Aged, Animals, Female, Humans, Male, Mice, Middle Aged, Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Drug Resistance, Neoplasm, Genetic Therapy, Immune Checkpoint Inhibitors, Mesothelioma, Malignant, Nivolumab, Pleural Neoplasms, Tumor Microenvironment

Published Open-Access

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