A Phase 2, Open-Label, Single-Center Study of Ad-SGE-DKK3 Gene Therapy in Combination with Nivolumab in Patients with Chemotherapy-Refractory Epithelioid Pleural Mesothelioma
Presented During:
Saturday, May 6, 2023: 8:00AM - Tuesday, May 9, 2023: 11:45AM
Los Angeles Convention Center
Posted Room Name:
Outside of Room 408
Abstract No:
LB010
Submission Type:
Late-Breaking Clinical Trial Abstract
Authors:
Hyun-Sung Lee (1), Bryan Burt (1), Hee-Jin Jang (1), Daniel Wang (1), Meera Patel (1), Maheshwari Ramineni (1), Monica Espinoza (1), Daniela Ramos (1), Jong Min Choi (1), Sung Wook Kang (1), Michelle Almarez (1), leandria hosey (1), Claire Lee (1), Michelle Ngo (1), Peter Jindra (1), R. Taylor Ripley (1)
Institutions:
(1) Baylor College of Medicine, Houston, TX
Submitting Author:
*Hyun-Sung Lee
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Baylor College of Medicine
Baylor College of Medicine
Co-Author(s):
*Bryan Burt
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Baylor College of Medicine
Baylor College of Medicine
Hee-Jin Jang
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Baylor College of Medicine
Baylor College of Medicine
Daniel Wang
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Baylor College of Medicine
Baylor College of Medicine
Meera Patel
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Baylor College of Medicine
Baylor College of Medicine
Maheshwari Ramineni
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Baylor College of Medicine
Baylor College of Medicine
Monica Espinoza
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Baylor College of Medicine
Baylor College of Medicine
Daniela Ramos
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Baylor College of Medicine
Baylor College of Medicine
Jongmin Choi
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Baylor College of Medicine
Baylor College of Medicine
Sung Wook Kang
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Baylor College of Medicine
Baylor College of Medicine
Michelle Almarez
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Baylor College of Medicine
Baylor College of Medicine
leandria hosey
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Baylor College of Medicine
Baylor College of Medicine
Claire Lee
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Baylor College of Medicine
Baylor College of Medicine
Michelle Ngo
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Baylor College of Medicine
Baylor College of Medicine
Peter Jindra
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Baylor College of Medicine
Baylor College of Medicine
*Robert Ripley
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Baylor College of Medicine
Baylor College of Medicine
Presenting Author:
*Bryan Burt
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Baylor College of Medicine
Baylor College of Medicine
Abstract:
Objective: Our preclinical studies have demonstrated that loss of secretory Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) results in immune evasion and that restoring tumoral DKK3 can sensitize the tumor microenvironment of malignant pleural mesothelioma (MPM) to checkpoint immunotherapy. Here, we present the results of phase 2 study of Ad-SGE-DKK3 gene therapy, a replication-incompetent adenovirus containing the DKK3 gene, in combination with nivolumab in patients with chemotherapy-refractory epithelioid MPM (NCT04013334).
Methods: Patients with epithelioid MPM refractory to pemetrexed-platin-based chemotherapy were treated with CT-guided intratumoral injections of Ad-SGE-DKK3 on Days 1, 8, 22, and 50 and 480mg nivolumab intravenously every 4 weeks until disease progression (Fig.1A). The primary objective was to determine objective response rate (ORR). Secondary and exploratory objectives included safety, rate of durable clinical benefit (DCB), survival, and alteration of tumor and serum biomarkers.
Results: Sixteen patients were screened for eligibility and 12 patients were enrolled between 2019 and 2022. Nine patients (75%) completed four injections of Ad-SGE-DKK3. Three patients received at least one injection of Ad-SGE-DKK3 but discontinued treatment due to disease progression (n=2) or COVID-19 infection (n=1). Two patients (16.6%) had a partial response (PR) and five (41.7%) had stable disease (SD), as the best response within the 6-month treatment timeframe (Fig.1B-C), with a DCB (PR+SD) rate of 58.3%. At 17.8 months follow-up, median overall survival and median progression-free survival were 14.5 months and 4.5 months, respectively (Fig.1D). Grade 3 adverse events developed in 5 patients (41.7%). Imaging mass cytometry on serial tumor biopsy samples (Fig.1E-F) revealed that tumor-infiltrating CD8 T cells significantly increased after treatment (Fig.1G) and that activated and memory CD8 T cells were abundant in on-treatment tumors (Fig.1H). Immunoassays in serum showed that DCB patients had lower pre-treatment levels of IL-6 and M-CSF than patients with progressive disease and sustained lower concentrations of soluble PD-L1 and M-CSF than progressors. Soluble PD-1 was significantly decreased after treatment in both groups (Fig.1I).
Conclusions: Intratumoral administration of Ad-SGE-DKK3 combined with immune checkpoint blockade showed a favorable safety profile and promising efficacy in patients with chemotherapy-refractory epithelioid MPM.
Methods: Patients with epithelioid MPM refractory to pemetrexed-platin-based chemotherapy were treated with CT-guided intratumoral injections of Ad-SGE-DKK3 on Days 1, 8, 22, and 50 and 480mg nivolumab intravenously every 4 weeks until disease progression (Fig.1A). The primary objective was to determine objective response rate (ORR). Secondary and exploratory objectives included safety, rate of durable clinical benefit (DCB), survival, and alteration of tumor and serum biomarkers.
Results: Sixteen patients were screened for eligibility and 12 patients were enrolled between 2019 and 2022. Nine patients (75%) completed four injections of Ad-SGE-DKK3. Three patients received at least one injection of Ad-SGE-DKK3 but discontinued treatment due to disease progression (n=2) or COVID-19 infection (n=1). Two patients (16.6%) had a partial response (PR) and five (41.7%) had stable disease (SD), as the best response within the 6-month treatment timeframe (Fig.1B-C), with a DCB (PR+SD) rate of 58.3%. At 17.8 months follow-up, median overall survival and median progression-free survival were 14.5 months and 4.5 months, respectively (Fig.1D). Grade 3 adverse events developed in 5 patients (41.7%). Imaging mass cytometry on serial tumor biopsy samples (Fig.1E-F) revealed that tumor-infiltrating CD8 T cells significantly increased after treatment (Fig.1G) and that activated and memory CD8 T cells were abundant in on-treatment tumors (Fig.1H). Immunoassays in serum showed that DCB patients had lower pre-treatment levels of IL-6 and M-CSF than patients with progressive disease and sustained lower concentrations of soluble PD-L1 and M-CSF than progressors. Soluble PD-1 was significantly decreased after treatment in both groups (Fig.1I).
Conclusions: Intratumoral administration of Ad-SGE-DKK3 combined with immune checkpoint blockade showed a favorable safety profile and promising efficacy in patients with chemotherapy-refractory epithelioid MPM.
Category:
Thoracic
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