Inhalation Therapy for Lung Cancer ‘Primed for Growth,’ Investigator Says

NEW YORK-Inhalationtherapy for lung cancer, explored formore than a decade, "is now primedfor growth," according to RomanPerez-Soler, MD. "There's a strongrationale for use of inhaled therapy incertain forms of lung cancer and lungpremalignancy," he said. "And there'spreliminary evidence of technical feasibilityand clinical activity; it's probably still anecdotal, but there are severaltrials all reporting some type ofresponse."Dr. Perez-Soler, professor of medicineand chairman and director ofmedical oncology, Montefiore MedicalCenter/Albert Einstein College ofMedicine, Bronx, New York, has over20 years' research experience in liposomaldrug delivery. He spoke aboutthe current state of investigation intoinhaled liposomal therapy for lungcancer at the 10th International Conferenceon Screening for Lung Cancer,hosted by Weill Medical Collegeof Cornell University.During the 10- to 25-year gestationperiod of lung cancer, he noted,the bronchial epithelium is attackedby inhaled carcinogens causing sequentialhistological damage also associatedwith specific genetic molecularabnormalities. "As the lesionsbecome detectable in increasinglysmaller sizes, it makes sense to thinkthat maybe we can intervene directlywith an inhaled therapeutic agent,"Dr. Perez-Soler said.Increasingly, he said, clinicians areseeing bronchoalveolar carcinoma,"an enigmatic form of lung cancer"that tends to be multifocal, multinodular,and with tiny bilateral lesionsthat are detected relatively early.Because of the size of the lesions,inhaled treatment could be more effectiveand perhaps prevent diseaseprogression.In bronchoalveolar cancer, Dr.Perez-Soler explained, while the surfaceof the alveoli is malignant, thecells do not tend to grow and coalesceinto a solid mass. Because the lesionsare not very thick, multiple inhalationtreatments could result in a "peelingoff" of the lesion. The inhalationmode is expected to be more effectivethan systemic therapy through thecapillaries, where the drug has to diffusethrough the vessels to the surfaceof the epithelium.The inhalation therapy benefit ofdirect drug delivery to the bronchoalveolarepithelium and lung parenchymais well known; experimentshave shown that only about 1% of anintravenously injected dose reaches the lung parenchyma vs 15% to 20%when the drug is administered via aregular nebulizer, he said. Anotherbenefit is the reduced toxicity thatcomes with reduced systemic distribution.A third potential advantageof inhalation therapy is the possiblepreferential delivery of the agent tothe regional lymphatic system.Variety of Agents TestedOver the past 10 years, mostly insmall studies of lung and other cancers,Dr. Perez-Soler said, inhaledtherapy has been tested using a varietyof cytotoxic agents, including fluorouracil,doxorubicin, cisplatin(Platinol), and paclitaxel. In almostall of those studies, responses werereported.Differentiating agents have alsobeen studied as inhaled therapy inlung cancer, and at least seven haveshown clinical activity: interleukin-2,interferon, GM-CSF, hypomethylatingagents, cyclo-oxygenase-2 (COX-2) inhibitors, epithelial growth factorreceptor (EGFR) inhibitors, andproteasome inhibitors.Dr. Perez-Soler and his colleagueshave worked with biotechnologyresearchers at Transave Inc.(Monmouth Junction, New Jersey)over the last few years, to optimizeinhalation therapeutics for lung cancer.Together, they developed Sustainedrelease Lipid Inhalation Targetingtechnology, or SLIT, toimprove current injectable or inhaledproducts by producing a targeted,prolonged therapeutic effect in thelung that reduces systemic and localtoxicity, and permits dose reduction.Transave has sponsored a phase Istudy of SLIT with cisplatin, conductedby Pieter E. Postmus, MD, PhD,of the Department of Pulmonology,Free University Hospital, Amsterdam,Netherlands. So far, Dr. Postmus hasbeen able to escalate to an inhaledliposomal cisplatin dose of 48 mg/m²every 2 weeks or 24 mg/m² every week,similar to intravenous doses, withoutreaching dose-limiting toxicity."There has been some nausea andvomiting, but basically cisplatin canbe given easily by inhalation withoutcausing any irritation," Dr. Perez-Soler said.In about 50% of lung cancers and15% of severe dysplasias, p53 functionis lost because of a mutation; ifp53 function can be restored in thoselesions, apoptosis can be induced. Dr.Perez-Soler and his coworkers expectto initiate a study of inhaled p53 in aliposome carrier later this year. Priorsimilar work includes that of DavidCarbone, MD, of Vanderbilt-IngramCancer Center, in which p53 was administeredin adenovirus intra-bronchiallyand well-tolerated in patientswith bronchoalveolar carcinoma.Dr. Perez-Soler's team assessed theeffects of direct intratracheal administrationof the p53 gene in a cationiclipid vector in a mouse model of lungcancer. Treatment was given on days4, 8, 12, 16, and 20. Histological analysisof animals sacrificed approximately6 weeks after the start of treatmentshowed that liposomal p53 gene therapyhad prevented tumor growth inthe lung bilaterally and led to longersurvival, compared with controls.The investigators confirmed theseresults using the same formulation asinhaled therapy. They have finishedpreclinical toxicology studies of thiscationic lipid polymer p53 gene therapyand expect to initiate further studiesat Albert Einstein College of Medicinein the second half of 2004."Inhalatory therapies for lung cancerare still a relatively new field," heconcluded. "There is a lot of work tobe done, basically optimizing theagents; selecting the correct agent; andselecting the right delivery system,dose, schedule, and nebulizer, beforewe can embark on comparative efficacystudies."