A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses.
OBJECTIVE
This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE).


METHODS
Ad.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) 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-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 10(12) 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-beta 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-beta 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.
Thoracic Oncology Gene Therapy Program and Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4283, USA. sterman@mail.med.upenn.edu
Daniel H
DH
Sterman
Adri
A
Recio
Richard G
RG
Carroll
Colin T
CT
Gillespie
Andrew
A
Haas
Anil
A
Vachani
Veena
V
Kapoor
Jing
J
Sun
Richard
R
Hodinka
Jennifer L
JL
Brown
Michael J
MJ
Corbley
Michael
M
Parr
Mitchell
M
Ho
Ira
I
Pastan
Michael
M
Machuzak
William
W
Benedict
Xin-qiao
XQ
Zhang
Elaina M
EM
Lord
Leslie A
LA
Litzky
Daniel F
DF
Heitjan
Carl H
CH
June
Larry R
LR
Kaiser
Robert H
RH
Vonderheide
Steven M
SM
Albelda
Michelle
M
Kanther
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016899:Interferon-beta / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008654:Mesothelioma / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D016066:Pleural Effusion, Malignant / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D010997:Pleural Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000970:Antineoplastic Agents; D016207:Cytokines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016899:Interferon-beta