TY - JOUR
T1 - Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy
AU - Sterman, Daniel H.
AU - Alley, Evan
AU - Stevenson, James P.
AU - Friedberg, Joseph
AU - Metzger, Susan
AU - Recio, Adri
AU - Moon, Edmund K.
AU - Haas, Andrew R.
AU - Vachani, Anil
AU - Katz, Sharyn I.
AU - Sun, Jing
AU - Heitjan, Daniel F.
AU - Hwang, Wei Ting
AU - Litzky, Leslie
AU - Yearley, Jennifer H.
AU - Tan, Kay See
AU - Papasavvas, Emmanouil
AU - Kennedy, Paul
AU - Montaner, Luis J.
AU - Cengel, Keith A.
AU - Ii, Charles B.Simone
AU - Culligan, Melissa
AU - Langer, Corey J.
AU - Albelda, Steven M.
N1 - Publisher Copyright:
©2016 American Association for Cancer Research.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Purpose: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. Experimental Design: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured. Results: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. Conclusions: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemoimmunogene therapy versus standard chemotherapy alone.
AB - Purpose: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. Experimental Design: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured. Results: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. Conclusions: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemoimmunogene therapy versus standard chemotherapy alone.
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U2 - 10.1158/1078-0432.CCR-15-2133
DO - 10.1158/1078-0432.CCR-15-2133
M3 - Article
C2 - 26968202
AN - SCOPUS:84980426841
SN - 1078-0432
VL - 22
SP - 3791
EP - 3800
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -