Novel Therapies for CF, Lung Infection, and Lung Cancer Show Early Promise

SAN DIEGO—From aerosolized delivery systems for cystic fibrosis (CF) and lung infections to stem cell therapy for lung cancer, novel treatments for these pulmonary disorders are showing promise in the early stages of testing. Researchers presented their latest findings on these emerging therapies at the 2009 International Conference of the American Thoracic Society, and discussed how the treatments may improve upon the limitations that come with currently available options.

AEROSOLIZED THERAPY FOR CF

Andrew J. Hirsh, MD, Senior Director of Drug Discovery and Preclinical Development at Parion Sciences Inc, Durham, North Carolina, described positive results from in vitro studies and an animal model of an aerosolized form of pharmacotherapy called GS-9411 (formerly named P-680) for patients with CF. GS-9411—an epithelial sodium channel blocker currently being tested in phase I clinical trials—is designed to restore and normalize the airway surface liquid and improve mucociliary clearance, Dr. Hirsh explained. The treatment has the potential to decrease pulmonary exacerbations and improve lung function in these patients to a degree not currently seen with amiloride, a well-recognized epithelial sodium channel blocker. Prior research has shown amiloride to fail as an aerosol therapy for CF due to poor intrinsic activity, a rapid off-rate from the channel, and rapid absorption by the airway epithelia.

In preclinical studies, Dr. Hirsh and colleagues tested GS-9411 for its durability in blocking the sodium channel, using amiloride as a comparator. Key issues facing the researchers included how to maximize drug efficacy and minimize potential toxicity using a selective criteria: how potent is the drug, how tightly bound GS-9411is to its protein target, and how quickly the drug would be absorbed across the epithelium.

The in vitro results showed that compared with amiloride, GS-9411 was 100 times more potent, 400 times more tightly bound to its target protein, and two times slower at crossing the airway epithelia than amiloride.

But would all of those attributes actually create a greater surface liquid layer and thus indicate whether mucociliary clearance could be increased (both essential aspects to treating CF)? Further in vitro analysis revealed that GS-9411 rapidly increased airway surface liquid and retained surface liquid expansion for eight hours. The novel therapy demonstrated 60% to 75% fluid retention, while amiloride showed 10% to 25%, Dr. Hirsh said.

“This suggests that these attributes do have an effect overall on the surface liquid,” he explained. “Therefore, GS-9411 could contribute to increasing mucociliary clearance. By rehydrating the airway surface liquid, you allow cilia to clear the mucus and bacteria out of the lung.”

In addition to in vitro studies, an in vivo sheep model was used to further evaluate GS-9411. Results from this experiment showed a significant increase in mucociliary clearance using aerosolized GS-4911, compared with amiloride. The novel therapy enhanced mucous clearance for four to five hours. These results—which eventually led to its current status as a treatment being tested in Phase I clinical trials with healthy human volunteers—gave Dr. Hirsh and colleagues “great hope that this drug would be beneficial in cystic fibrosis.”

ANTIMICROBIALS VIA NANOPARTICLES FOR PULMONARY INFECTIONS

An aerosol also could be used to deliver new therapies for patients with pneumonia, said Carolyn L. Cannon, MD, PhD, Assistant Professor of Pediatrics at the Washington University School of Medicine in St. Louis.

She described how a novel class of broad-spectrum antimicrobials called silver carbene complexes (SCCs) could potentially treat lung infections in humans. Many SCCs are water soluble, thus allowing them to be nebulized for drug delivery. Dr. Cannon and her research team are developing one such compound, SCC1. They hypothesize that depot delivery of SCCs may increase dosing intervals and hence patient compliance. An in vivo study in mice using a clinical strain of Pseudomonas aeruginosa isolated from the lungs of a CF patient showed clinical improvement with SCC1 compared with nebulized tobramycin at a dosing interval of 12 hours.

In the present study, Dr. Cannon and colleagues initially sought to experiment with aerolized SCC1 but could not load that compound into the nanoparticles due to technical reasons. Instead, SCC22, a compound with similar antimicrobial properties but with characteristics more amenable to loading was successfully loaded into aerosolized nanoparticles formulated from either L-tyrosine polyphosphate (LTP) or poly(lactic-co-glycolic acid). Mice infected with P aeruginosa received either SCC22-loaded particles or empty nanoparticles once daily. Results showed that while all untreated mice died, all those that received treatment with SCC22-loaded LTP nanoparticles survived. Compared with untreated mice, treated mice also exhibited decreased weight loss and a reduction in bacterial burden and in the spread of bacteria from the lung into the bloodstream reaching the spleen, compared with untreated mice.

The researchers achieved a successful 24-hour dosing interval in their mouse model with SCC22-loaded LTP nanoparticles, providing a survival advantage similar to that of SCC1, with a reduced amount of SCCs and half the number of doses. These results suggest that this treatment option may provide effective and sustained antimicrobial therapy, the researchers concluded.

“In our view, SCC-loaded nanoparticles administered via nebulization on a once-daily basis epitomized convenient and effective drug delivery and encourages patient compliance, thereby ensuring successful treatment,” Dr. Cannon said. “We believe we are close to realizing our aim of developing broad-spectrum, long-acting antibiotics for the treatment of pulmonary infections. We are eager to complete studies that would enable us to apply for investigational new drug status to commence clinical trials.”

Dr. Cannon explained that broad spectrum of SCCs and nanoparticle activity allows this therapy to “have a pronounced effect on human health and the treatment of lung infections. The effectiveness and ease of manufacturing will make SCCs of critical importance in addressing global health challenges.” She remarked that she and her team hope to eventually load SCC1 into aerolized nanoparticles.

"SEEK AND DESTROY" CANCER

Novel therapies are also being developed in the field of lung cancer, where currently available treatments often have poor tolerability profiles. Michael R. Loebinger, MD, of the Centre for Respiratory Research at the University College London, discussed how a combined approach of adult stem cell therapy and cancer-seeking agents may avoid the “sledgehammer effect” of chemotherapy and radiotherapy, which harms both cancerous and normal cells.

Dr. Loebinger and Sam M. Janes, MD, PhD, also of University College London, made use of mesenchymal stem cells from human bone marrow in their research, “which have an innate ability to home toward tumors throughout the body.” These cells then were engineered to produce an anti-cancer protein known as a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). He coined this combined therapy a “seek out and destroy” approach.

“These TRAIL-expressing stem cells home toward tumors armed with something which can specifically kill the cancer cells, leaving normal cells relatively intact,” Dr. Loebinger said.

The in vitro portion of the study demonstrated that this therapy kills tumor cells resistant to certain currently available chemotherapy regimens. During the experiment with an in vivo mouse model of lung metastatic cancer, both the size and number of multiple lung tumors were reduced with the use of TRAIL stem cell therapy; in three of the eight mice, tumors were fully destroyed.

TRAIL is being used in clinical trials as an intravenous drug or as a monoclonal antibody, Dr. Loebinger pointed out, and has been shown in phase I and II trials to be safe and beneficial to patients. In prior research, mesenchymal cells have been used to treat various human diseases, such as cardiac disorders. Dr. Loebinger’s study was the first to show a significant reduction in tumor burden using the two approaches—TRAIL as a cancer treatment and intravenously-delivered adult mesenchymal stem cells to home to tumors. He is hopeful that the success seen in this study will help pave the way for testing this in human safety trials.

“There is some hope that it will have some effect against resistant tumors, and it also can be administered in addition to chemotherapy,” Dr. Loebinger said. However, key questions still remain regarding the timing and dosage of TRAIL delivery, as well as the specific role that mesenchymal cells play in cancer therapy beyond being an inert vehicle.

—John Merriman

Suggested Reading
Cannon CL, Hogue LA, Vajravelu R, et al. Nebulized SCC1, a methylated caffeine - silver (I) complex, for treatment of pulmonary infections: in vitro and murine efficacy and toxicity studies. Antimicrob Agents Chemother. 2009; May 18 [Epub ahead of print].
Hirsh AJ, Zhang J, Zamurs A, et al. Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N’-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02), a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease. J Pharmacol Exp Ther. 2008;325(1):77-88.
Loebinger MR, Eddaoudi A, Davies D, Janes SM. Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res. 2009;69(10):4134-4142.

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