caa a22 4500 397563000 CHVBK 20180308164821.0 cr unu---uuuuu 161202e19961218xx s 000 0 eng 10.1093/jnci/88.24.1857 doi (NATIONALLICENCE)oxford-10.1093/jnci/88.24.1857 Phase I Study of a Recombinant Adenovirus-Mediated Gene Transfer in Lung Cancer Patients [Elektronische Daten] [Thomas Tursz, Axel Le Cesne, Pierre Baldeyrou, Eric Gautier, Paule Opolon, Christian Schatz, Andrea Pavirani, Michael Courtney, Didier Lamy, Thierry Ragot, Patrick Saulnier, Antoine Andremont, Roger Monier, Michel Perricaudet, Thierry Le Chevalier] Background Despite vigorous efforts at curbing tobacco consumption and aggressive combined-modality treatment programs, both the incidence of and the mortality from lung cancer have remained virtually unchanged in the last 10 years. More effective innovative therapies are clearly needed. The direct transfer into tumor cells of tumor suppressor genes or toxic gene products that specifically promote tumor cell death and spare nonmalignant cells is a potentially novel anticancer treatment approach that should be investigated. Purpose: On the basis of compelling preclinical data, we initiated a phase I study involving six patients with inoperable lung cancer and an endobronchial lesion accessible by bronchoscopy. Our purpose was to evaluate the feasibility, tolerance, and clinical, biologic, and immunologic effects of the intratumoral administration of a recombinant, replication-deficient adenovirus (rAd.RSVβ-gal), using the Rous sarcoma virus promoter to drive transcription of the Escherichia coli lacZ marker gene that encodes for the bacterial enzyme β-galactosidase (β-gal). Methods From June 1994 through April 1995, six patients (five males and one female) were enrolled in the trial. A single dose of recombinant virus suspension containing 107 or 108 plaque-forming units (PFU) was injected intratumorally into two successive cohorts of three patients. Eligible patients received concomitant chemotherapy. Patients were kept under isolation conditions from 3 days before the injection was given until virus excretion was undetectable. Biopsyspecimens of the tumor and surrounding mucosa were collected on the 8th day and at 1, 2, and 3 months after injection. They were analyzed by cell culture, polymrase chain reaction (PCR), and β-gal expression for the presence of recombinant adenovirus. So that the risk of virus recombination or complementation could be minimized, wild-type adenovirus carriers among the hospital staff (identified by PCR) were excluded from contact with patients who were potentially excreting recombinant virus. Results β-gal was expressed in tumor biopsy specimens of three patients (one who received the 107 PFU dose level and two who received 108). Bronchoalveolar lavage specimens collected immediately after injection were positive for recombinant adenovirus when analyzed in culture and by PCR. All biologic fluids were negative for recombinant virus as judged by PCR after day 12, with the exception of bronchoalveolar lavage specimens (positive PCR up to 90 days in two of three patients treated with 108 PFU). The blood samples obtained from the three patients treated with 108 PFU showed positive PCR results immediately after virus injection. Patients were kept in isolation for a median of 17 days. The most common toxic effects were moderate bleeding (occurring in two patients) during bronchoscopy and fever (seen in four patients). Endoscopic and clinically objective antitumor responses were seen in four patients, including one patient who showed a complete response by pathologic evaluation. The median survival for the patients was 12.5 months (range, 3-16+ months). Throughout the study, hospital staff remained negative for recombinant adenovirus infection. Conclusions This ongoing phase I study has demonstrated that a recombinant adenovirus-mediated marker gene, such as rAd.RSVβ-gal, can be safely introduced into humans and that the gene product is expressed by lung tumor cells of the host. [J Natl cancer Inst 1996;88:1857-63] © Oxford University Press REPORTS nationallicence Tursz Thomas Institut Gustave-Roussy Villejuif, France aut Le Cesne Axel Institut Gustave-Roussy Villejuif, France aut Baldeyrou Pierre Institut Gustave-Roussy Villejuif, France aut Gautier Eric Institut Gustave-Roussy Villejuif, France aut Opolon Paule Institut Gustave-Roussy Villejuif, France aut Schatz Christian Transgene, Strasbourg, France aut Pavirani Andrea Transgene, Strasbourg, France aut Courtney Michael Transgene, Strasbourg, France aut Lamy Didier Transgene, Strasbourg, France aut Ragot Thierry Institut Gustave-Roussy Villejuif, France aut Saulnier Patrick Institut Gustave-Roussy Villejuif, France aut Andremont Antoine Institut Gustave-Roussy, Villejuif, France aut Monier Roger Institut Gustave-Roussy Villejuif, France aut Perricaudet Michel Institut Gustave-Roussy Villejuif, France aut Le Chevalier Thierry Institut Gustave-Roussy Villejuif, France aut JNCI: Journal of the National Cancer Institute Oxford University Press 88/24(1996-12-18), 1857-1863 0027-8874 88:24<1857 1996 88 jnci https://doi.org/10.1093/jnci/88.24.1857 text/html Onlinezugriff via DOI 1 brief-communication jats NATIONALLICENCE 856 40 https://doi.org/10.1093/jnci/88.24.1857 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tursz Thomas Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Le Cesne Axel Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Baldeyrou Pierre Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Gautier Eric Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Opolon Paule Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Schatz Christian Transgene, Strasbourg, France aut NATIONALLICENCE 700 1- Pavirani Andrea Transgene, Strasbourg, France aut NATIONALLICENCE 700 1- Courtney Michael Transgene, Strasbourg, France aut NATIONALLICENCE 700 1- Lamy Didier Transgene, Strasbourg, France aut NATIONALLICENCE 700 1- Ragot Thierry Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Saulnier Patrick Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Andremont Antoine Institut Gustave-Roussy, Villejuif, France aut NATIONALLICENCE 700 1- Monier Roger Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Perricaudet Michel Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 700 1- Le Chevalier Thierry Institut Gustave-Roussy Villejuif, France aut NATIONALLICENCE 773 0- JNCI: Journal of the National Cancer Institute Oxford University Press 88/24(1996-12-18), 1857-1863 0027-8874 88:24<1857 1996 88 jnci Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford