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. Cengel & 4 others Charles B.Simone Ii, Melissa Culligan, Corey J. Langer, Steven M. Albelda

Research output: Contribution to journalArticle

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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

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Adenoviridae
Genetic Therapy
Celecoxib
Drug Therapy
Pemetrexed
gemcitabine
Survival
Histology
Regulatory T-Lymphocytes
Natural Killer Cells
Genes
Disease-Free Survival
Malignant Mesothelioma
Immune System
Blood Cells
Vaccination
Research Design
Therapeutics
Randomized Controlled Trials
T-Lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy. / 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.; Ii, Charles B.Simone; Culligan, Melissa; Langer, Corey J.; Albelda, Steven M.

In: Clinical Cancer Research, Vol. 22, No. 15, 01.08.2016, p. 3791-3800.

Research output: Contribution to journalArticle

Sterman, DH, Alley, E, Stevenson, JP, Friedberg, J, Metzger, S, Recio, A, Moon, EK, Haas, AR, Vachani, A, Katz, SI, Sun, J, Heitjan, DF, Hwang, WT, Litzky, L, Yearley, JH, Tan, KS, Papasavvas, E, Kennedy, P, Montaner, LJ, Cengel, KA, Ii, CBS, Culligan, M, Langer, CJ & Albelda, SM 2016, 'Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy', Clinical Cancer Research, vol. 22, no. 15, pp. 3791-3800. https://doi.org/10.1158/1078-0432.CCR-15-2133
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. ; Ii, Charles B.Simone ; Culligan, Melissa ; Langer, Corey J. ; Albelda, Steven M. / Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNa combined with chemotherapy. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 15. pp. 3791-3800.
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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.",
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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.

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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