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.
Sterman
Daniel H
DH
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
Recio
Adri
A
Carroll
Richard G
RG
Gillespie
Colin T
CT
Haas
Andrew
A
Vachani
Anil
A
Kapoor
Veena
V
Sun
Jing
J
Hodinka
Richard
R
Brown
Jennifer L
JL
Corbley
Michael J
MJ
Parr
Michael
M
Ho
Mitchell
M
Pastan
Ira
I
Machuzak
Michael
M
Benedict
William
W
Zhang
Xin-qiao
XQ
Lord
Elaina M
EM
Litzky
Leslie A
LA
Heitjan
Daniel F
DF
June
Carl H
CH
Kaiser
Larry R
LR
Vonderheide
Robert H
RH
Albelda
Steven M
SM
Kanther
Michelle
M
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