A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions

High rate of antitumor immune responses

Daniel H. Sterman, Adri Recio, Richard G. Carroll, Colin T. Gillespie, Andrew Haas, Anil Vachani, Veena Kapoor, Jing Sun, Richard Hodinka, Jennifer L. Brown, Michael J. Corbley, Michael Parr, Mitchell Ho, Ira Pastan, Michael Machuzak, William Benedict, Xin Qiao Zhang, Elaina M. Lord, Leslie A. Litzky, Daniel F. Heitjan & 4 others Carl H. June, Larry R. Kaiser, Robert H. Vonderheide, Steven M. Albelda

Research output: Contribution to journalArticle

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Abstract

Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). Experimental Design: Ad.IFN-β was administered through an in dwelling pleural catheter in doses ranging from 9 × 1011to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

Original languageEnglish (US)
Pages (from-to)4456-4466
Number of pages11
JournalClinical Cancer Research
Volume13
Issue number15
DOIs
StatePublished - Aug 1 2007

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Clinical Trials, Phase I
Pleural Effusion
Genes
Virion
Malignant Mesothelioma
Cytokines
Patient Participation
Lymphopenia
Indwelling Catheters
Simian virus 40
Maximum Tolerated Dose
Viral Tumor Antigens
Neoplasm Antigens
Natural Killer Cells
Positron-Emission Tomography
Research Design
Thorax
Tomography

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions : High rate of antitumor immune responses. / Sterman, Daniel H.; Recio, Adri; Carroll, Richard G.; Gillespie, Colin T.; Haas, Andrew; Vachani, Anil; Kapoor, Veena; Sun, Jing; Hodinka, Richard; Brown, Jennifer L.; Corbley, Michael J.; Parr, Michael; Ho, Mitchell; Pastan, Ira; Machuzak, Michael; Benedict, William; Zhang, Xin Qiao; Lord, Elaina M.; Litzky, Leslie A.; Heitjan, Daniel F.; June, Carl H.; Kaiser, Larry R.; Vonderheide, Robert H.; Albelda, Steven M.

In: Clinical Cancer Research, Vol. 13, No. 15, 01.08.2007, p. 4456-4466.

Research output: Contribution to journalArticle

Sterman, DH, Recio, A, Carroll, RG, Gillespie, CT, Haas, A, Vachani, A, Kapoor, V, Sun, J, Hodinka, R, Brown, JL, Corbley, MJ, Parr, M, Ho, M, Pastan, I, Machuzak, M, Benedict, W, Zhang, XQ, Lord, EM, Litzky, LA, Heitjan, DF, June, CH, Kaiser, LR, Vonderheide, RH & Albelda, SM 2007, 'A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: High rate of antitumor immune responses', Clinical Cancer Research, vol. 13, no. 15, pp. 4456-4466. https://doi.org/10.1158/1078-0432.CCR-07-0403
Sterman, Daniel H. ; Recio, Adri ; Carroll, Richard G. ; Gillespie, Colin T. ; Haas, Andrew ; Vachani, Anil ; Kapoor, Veena ; Sun, Jing ; Hodinka, Richard ; Brown, Jennifer L. ; Corbley, Michael J. ; Parr, Michael ; Ho, Mitchell ; Pastan, Ira ; Machuzak, Michael ; Benedict, William ; Zhang, Xin Qiao ; Lord, Elaina M. ; Litzky, Leslie A. ; Heitjan, Daniel F. ; June, Carl H. ; Kaiser, Larry R. ; Vonderheide, Robert H. ; Albelda, Steven M. / A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions : High rate of antitumor immune responses. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 15. pp. 4456-4466.
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abstract = "Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). Experimental Design: Ad.IFN-β was administered through an in dwelling pleural catheter in doses ranging from 9 × 1011to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.",
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T1 - A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions

T2 - High rate of antitumor immune responses

AU - Sterman, Daniel H.

AU - Recio, Adri

AU - Carroll, Richard G.

AU - Gillespie, Colin T.

AU - Haas, Andrew

AU - Vachani, Anil

AU - Kapoor, Veena

AU - Sun, Jing

AU - Hodinka, Richard

AU - Brown, Jennifer L.

AU - Corbley, Michael J.

AU - Parr, Michael

AU - Ho, Mitchell

AU - Pastan, Ira

AU - Machuzak, Michael

AU - Benedict, William

AU - Zhang, Xin Qiao

AU - Lord, Elaina M.

AU - Litzky, Leslie A.

AU - Heitjan, Daniel F.

AU - June, Carl H.

AU - Kaiser, Larry R.

AU - Vonderheide, Robert H.

AU - Albelda, Steven M.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). Experimental Design: Ad.IFN-β was administered through an in dwelling pleural catheter in doses ranging from 9 × 1011to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

AB - Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). Experimental Design: Ad.IFN-β was administered through an in dwelling pleural catheter in doses ranging from 9 × 1011to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

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