PHASE-I STUDY OF A RECOMBINANT ADENOVIRUS-MEDIATED GENE-TRANSFER IN LUNG-CANCER PATIENTS

Background: Despite vigorous efforts at curbing tobacco consumption an d aggressive combined-modality treatment programs, both the incidence of and the mortality from lung cancer have remained virtually unchange d in the last 10 years. More effective innovative therapies are clearl y needed. The direct transfer into tumor cells of tumor suppressor gen es or toxic gene products that specifically promote tumor cell death a nd spare nonmalignant cells is a potentially novel anticancer treatmen t approach that should be investigated. Purpose: On the basis of compe lling preclinical data, we initiated a phase I study involving six pat ients with inoperable lung cancer and an endobronchial lesion accessib le by bronchoscopy. Our purpose was to evaluate the feasibility, toler ance, and clinical, biologic, and immunologic effects of the intratumo ral administration of a recombinant, replication-deficient adenovirus (rAd.RSV beta-gal), using the Rous sarcoma virus promoter to drive tra nscription of the Escherichia coli lacZ marker gene that encodes for t he bacterial enzyme beta-galactosidase (beta-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 10(7) or 10(8) plaque-forming units (PFU) was injected intr atumorally into two successive cohorts of three patients. Eligible pat ients received concomitant chemotherapy, Patients were kept under isol ation conditions from 3 days before the injection was given until viru s excretion was undetectable. Biopsy specimens of the tumor and surrou nding mucosa were collected on the 8th day and at 1, 2, and 3 months a fter injection, They were analyzed by cell culture, polymerase chain r eaction (PCR), and beta-gal expression for the presence of recombinant adenovirus. So that the risk of virus recombination or complementatio n could be minimized, wildtype adenovirus carriers among the hospital staff (identified by PCR) were excluded from contact with patients who were potentially excreting recombinant virus. Results: beta-gal was e xpressed in tumor biopsy specimens of three patients (one who received the 107 PFU dose level and two who received 10(8)). Bronchoalveolar l avage specimens collected immediately after injection were positive fo r recombinant adenovirus when analyzed in culture and by PCR, All biol ogic fluids were negative for recombinant virus as judged by PCR after day 12, with the exception of bronchoalveolar lavage specimens (posit ive PCR up to 90 days in two of three patients treated with 10(8) PFU) . The blood samples obtained from the three patients treated with 10(8 ) PFU showed positive PCR results immediately after virus injection. P atients were kept in isolation for a median of 17 days. The most commo n toxic effects were moderate bleeding (occurring in two patients) dur ing bronchoscopy and fever (seen in four patients). Endoscopic and cli nically objective antitumor responses were seen in four patients, incl uding one patient who showed a complete response by pathologic evaluat ion. 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 st udy has demonstrated that a recombinant adenovirus-mediated marker gen e, such as rAd.RSV beta-gal, can be safely introduced into humans and that the gene product is expressed by lung tumor cells of the host.