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| Status |
Public on Jul 30, 2024 |
| Title |
Ad-SGE-DKK3 Gene Therapy Against Resistance to Immune Checkpoint Blockade in Malignant Mesothelioma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
This phase 2 study evaluates the combination of Ad-SGE-Dickkopf-3 (DKK3) gene therapy and nivolumab in patients with chemotherapy-refractory epithelioid malignant pleural mesothelioma (MPM). This clinical study was based on our preclinical study to overcome primary immune resistance by combining Ad-SGE-DKK3 gene therapy with anti-PD-1 therapy through DKK3-driven immune modulation in mesothelioma. The study enrolled 12 patients between 2019 and 2022, who were refractory to pemetrexed-platin-based chemotherapy. Treatment involved CT-guided intratumoral injections of Ad-SGE-DKK3 and systemic nivolumab administration. The primary goal was to assess the objective response rate (ORR), with secondary and exploratory objectives focusing on safety, durable clinical benefit (DCB), survival, and biomarker changes. Of the enrolled patients, 75% completed the Ad-SGE-DKK3 treatment protocol. The study observed a 16.6% ORR with 41.7% maintaining stable disease, which reached 58.3% DCB rate. The median overall survival was 14.5 months, and the median progression-free survival was 4.5 months. Adverse events of grade 3 were noted in 41.7% of patients. Serial analysis of tumor biopsies and serum biomarkers indicated that patients with DCB had increased tumor-infiltrating CD8 T cells, decreased circulating memory CD8 T cells, and sustained lower concentrations of soluble mesothelin and M-CSF than progressors. The combination therapy demonstrated a favorable safety profile and promising efficacy in this patient population. ClinicalTrials.gov identifier: NCT04013334
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| Overall design |
This phase 2 study evaluates the combination of Ad-SGE-Dickkopf-3 (DKK3) gene therapy and nivolumab in patients with chemotherapy-refractory epithelioid malignant pleural mesothelioma (MPM). This clinical study was based on our preclinical study to overcome primary immune resistance by combining Ad-SGE-DKK3 gene therapy with anti-PD-1 therapy through DKK3-driven immune modulation in mesothelioma. The study enrolled 12 patients between 2019 and 2022, who were refractory to pemetrexed-platin-based chemotherapy. Treatment involved CT-guided intratumoral injections of Ad-SGE-DKK3 and systemic nivolumab administration. The primary goal was to assess the objective response rate (ORR), with secondary and exploratory objectives focusing on safety, durable clinical benefit (DCB), survival, and biomarker changes. Of the enrolled patients, 75% completed the Ad-SGE-DKK3 treatment protocol. The study observed a 16.6% ORR with 41.7% maintaining stable disease, which reached 58.3% DCB rate. The median overall survival was 14.5 months, and the median progression-free survival was 4.5 months. Adverse events of grade 3 were noted in 41.7% of patients. Serial analysis of tumor biopsies and serum biomarkers indicated that patients with DCB had increased tumor-infiltrating CD8 T cells, decreased circulating memory CD8 T cells, and sustained lower concentrations of soluble mesothelin and M-CSF than progressors. The combination therapy demonstrated a favorable safety profile and promising efficacy in this patient population. ClinicalTrials.gov identifier: NCT04013334.
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| Contributor(s) |
Lee H, Burt B, Kang S |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jul 30, 2024 |
| Last update date |
Jul 31, 2024 |
| Contact name |
Sung Wook Kang |
| E-mail(s) |
u242688@bcm.edu
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| Phone |
504-826-0629
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| Organization name |
Baylor college of medicine
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| Department |
Surgery
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| Lab |
SOIL
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| Street address |
one plaza
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| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1141938 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE273448_RAW.tar |
19.6 Mb |
(http)(custom) |
TAR (of RESULTS) |
SRA Run Selector |
| Raw data are available in SRA |
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