Title: Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy.
Authors: Sterman, Daniel H; Alley, Evan; Stevenson, James P; Friedberg, Joseph; Metzger, Susan; Recio, Adri; Moon, Edmund K; Haas, Andrew R; Vachani, Anil; Katz, Sharyn I; Sun, Jing; Heitjan, Daniel F; Hwang, Wei-Ting; Litzky, Leslie; Yearley, Jennifer H; Tan, Kay See; Papasavvas, Emmanouil; Kennedy, Paul; Montaner, Luis J; Cengel, Keith A; Simone 2nd, Charles B; Culligan, Melissa; Langer, Corey J; Albelda, Steven M
Published In Clin Cancer Res, (2016 08 01)
Abstract: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system.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.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.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 chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791-800. ©2016 AACR.
PubMed ID:
26968202
MeSH Terms: Adenoviridae/genetics*; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols/adverse effects; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*; Combined Modality Therapy; Female; Genetic Therapy*/adverse effects; Genetic Therapy*/methods; Genetic Vectors/administration & dosage; Genetic Vectors/genetics*; Humans; Immunotherapy*/adverse effects; Immunotherapy*/methods; Interferon-alpha/genetics*; Lung Neoplasms/diagnosis; Lung Neoplasms/genetics*; Lung Neoplasms/mortality; Lung Neoplasms/therapy*; Male; Mesothelioma, Malignant; Mesothelioma/diagnosis; Mesothelioma/genetics*; Mesothelioma/mortality; Mesothelioma/therapy*; Middle Aged; Neoplasm Staging; Treatment Outcome