title: Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy.
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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Sterman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Evan
authors.initials: E
authors.lastname: Alley
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.affiliation: Division of Thoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Friedberg
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan
authors.initials: S
authors.lastname: Metzger
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Adri
authors.initials: A
authors.lastname: Recio
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Moon
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Haas
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.affiliation: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sharyn I
authors.initials: SI
authors.lastname: Katz
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Leslie
authors.initials: L
authors.lastname: Litzky
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kay See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Papasavvas
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Paul
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Cengel
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Simone
authors.affiliation: Division of Thoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Melissa
authors.initials: M
authors.lastname: Culligan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. albelda@mail.med.upenn.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D016898:Interferon-alpha / Q000235:genetics*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha