Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy

Daniel H. Sterman, Evan Alley, James P. Stevenson, Joseph Friedberg, Susan Metzger, Adri Recio, Edmund K. Moon, Andrew R. Haas, Anil Vachani, Sharyn I. Katz, Jing Sun, Daniel F. Heitjan, Wei Ting Hwang, Leslie Litzky, Jennifer H. Yearley, Kay See Tan, Emmanouil Papasavvas, Paul Kennedy, Luis J. Montaner, Keith A. CengelCharles B.Simone Ii, Melissa Culligan, Corey J. Langer, Steven M. Albelda

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3791-3800
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number15
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sterman, D. H., Alley, E., Stevenson, J. P., Friedberg, J., Metzger, S., Recio, A., Moon, E. K., Haas, A. R., Vachani, A., Katz, S. I., Sun, J., Heitjan, D. F., Hwang, W. T., Litzky, L., Yearley, J. H., Tan, K. S., Papasavvas, E., Kennedy, P., Montaner, L. J., ... Albelda, S. M. (2016). Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy. Clinical Cancer Research, 22(15), 3791-3800. https://doi.org/10.1158/1078-0432.CCR-15-2133