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Ad-SGE-DKK3 Gene Therapy Overcomes Resistance to Immune Checkpoint Blockade in Pleural Mesothelioma
Hee-Jin Jang1,2, Meera Patel2,3, Daniel Y Wang4
1David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
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.
Insights
This study shows that combining Ad-SGE-DKK3 with nivolumab may improve outcomes for patients with pleural mesothelioma resistant to chemotherapy. The treatment demonstrated potential efficacy and a tolerable safety profile in a Phase II trial.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Immune checkpoint inhibitors (ICIs) show limited effectiveness in treating pleural mesothelioma.
- Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) is a protein implicated in cancer progression and treatment resistance.
- Understanding DKK3's role is crucial for developing strategies to enhance ICI efficacy.
Purpose of the Study:
- To investigate the role of DKK3 in overcoming treatment resistance in pleural mesothelioma.
- To evaluate the efficacy and safety of a combination therapy involving Ad-SGE-DKK3 and nivolumab in patients with chemotherapy-refractory epithelioid pleural mesothelioma.
Main Methods:
- Preclinical studies were conducted to understand DKK3's function in ICI-resistant mesothelioma models.
- A single-arm, Phase II clinical trial was performed, administering intratumoral Ad-SGE-DKK3 and intravenous nivolumab.
- The primary endpoint for the clinical trial was the objective response rate (ORR).
Main Results:
- DKK3 was found to be downregulated in human epithelioid mesothelioma.
- DKK3 overexpression enhanced tumor immunogenicity by activating p53, increasing glycolysis, upregulating PD-L1, and reducing immunosuppressive factors.
- The Phase II trial reported an ORR of 16.6%, with 41.7% stable disease, achieving a 58.3% durable clinical response rate.
- Patients achieving durable response showed increased tumor-infiltrating CD8 T cells and reduced circulating memory CD8 T cells.
Conclusions:
- The combination of Ad-SGE-DKK3 and nivolumab shows promise as a tolerable and potentially effective treatment for chemotherapy-refractory epithelioid pleural mesothelioma.
- DKK3 manipulation can sensitize the tumor microenvironment, making it more responsive to immune checkpoint blockade.
- Further investigation is warranted to explore DKK3-based therapies for mesothelioma.
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