Expanding the Treatment Landscape for Nasal Polyps

From lab to bedside, Stella Lee, MD, is at the forefront of treatment for nasal polyps. Working primarily in chronic rhinosinusitis, she and her colleagues study novel immunotherapy drugs in clinical trials and investigate underlying disease drivers, environmental factors, and new technologies that could lead to improved treatment strategies.

Chronic rhinosinusitis affects five to 12 percent of people worldwide and is characterized by persistent inflammation of the sinonasal cavities. “My patients have difficulty breathing, smelling, tasting, and sleeping,” says Dr. Lee. “Given its prevalence and quality-of-life burden, this is an underappreciated condition with causes that are still poorly understood.”

Dr. Lee completed her residency in otolaryngology and head and neck surgery at Yale University, followed by a fellowship in rhinology and skull base surgery at Johns Hopkins University. She then joined the University of Pittsburgh Department of Otolaryngology as an assistant professor. 

Treatment for chronic rhinosinusitis, which can occur with or without nasal polyps, typically includes topical steroids, oral steroids, or endoscopic sinus surgery — one of the most common surgeries performed in the United States. Many patients experience postoperative recurrence of nasal polyps and may undergo multiple surgeries with no lasting relief. In recent years, however, promising immunotherapy approaches have emerged.

“The University of Pittsburgh was one of the first U.S. sites to participate in international multicenter clinical trials to provide novel immunomodulators for chronic rhinosinusitis,” says Dr. Lee. “We realized that if we could block the drivers of immunologic dysfunction, we would discover a more precise, less invasive way to treat our patients.”

First Immunotherapy Drug for Chronic Rhinosinusitis With Nasal Polyps

On the basis of clinical trial results from Pittsburgh and beyond, the U.S. Food and Drug Administration approved the first immunotherapy drug for chronic rhinosinusitis with nasal polyps in June of 2019. The drug, Dupixent (dupilumab), can produce dramatic results in some patients with severe disease. “Within two weeks some patients can smell again, they can taste again. Their polyps just melt away, the sinuses are clear, and the mucosa normalizes,” says Dr. Lee.

Dupixent targets interleukin (IL)-4 and IL-13, inhibiting the type-2 immune response thought to underlie many cases of chronic rhinosinusitis with nasal polyps. Dr. Lee is currently involved in clinical investigations of additional type-2-targeting drugs, such as omalizumab and benralizumab. Still, not all patients respond to these drugs, symptoms recur after treatment is discontinued, and biomarkers are needed to identify which patients are good candidates for which drugs.

“It is still undefined how these therapies will fit into the current armamentarium” says Dr. Lee. “Now having this experience with clinical trials for drugs developed elsewhere, we now have the bandwidth and capability to do our own clinical trials, with our own drug targets and our own methodology.”

Exploring the Potential of 15LO1 as a New Drug Target

For example, in collaboration with Sally Wenzel, MD, from the Division of Pulmonology, Allergy, and Critical Care Medicine at the University of Pittsburgh, and others, Dr. Lee currently is exploring the potential of 15-Lipoxygenase 1 (15LO1) as a new drug target. 15LO1 is a protein that acts downstream from IL-4 and IL-13 in the type-2 inflammatory cascade. In July of 2019, Dr. Lee, Dr. Wenzel, and colleagues reported in the Journal of Allergy and Clinical Immunology that 15LO1 is upregulated in nasal polyp cells sampled from patients with chronic rhinosinusitis. Inhibiting 15LO1 in these cells resulted in downstream inhibition of the inflammatory cascade.

“Our findings suggest that 15LO1 could be an even more specific drug target than IL-4 and IL-13. Now, we are using animal models to explore targeting 15LO1 with a small-molecule inhibitor,” says Dr. Lee. The new findings earned recognition as the best Basic Science Manuscript at the Rhinoworld conference in June 2019, an international meeting that is held every 10 years.
Meanwhile, Dr. Lee is examining the molecular underpinnings of chronic rhinosinusitis to tease apart the many mechanisms that are likely at play. These insights could reveal new biomarkers that could aid treatment decisions, and they could open up new therapeutic possibilities.

In this vein, she and her colleagues recently reported that a higher load of mast cells in surgically removed nasal polyp cells could predict a more recalcitrant postoperative disease course. Elevated mast cells could thus serve as a biomarker associated with diseaseseverity. This report — recognized as one of the Top 10 Clinical Abstracts at Rhinoworld 2019 — also suggests that mast cells may play an important underlying role in CRS pathogenesis.

Another recent project explored how to define subtypes of chronic rhinosinusitis with nasal polyps. “Not all nasal polyps are the same,” says Dr. Lee. Among several dozen patients who underwent endoscopic sinus surgery, she and her collaborators found that levels of several different cytokines in different nasal tissues correlated with different clinical outcomes. The findings point to distinct inflammation-driving mechanisms in different patients that could enable targeted treatment strategies that are individualized to the patient.

Connections Between Environmental Pollutants and Chronic Rhinosinusitis

In addition to the molecular facets of chronic rhinosinusitis, Dr. Lee is actively investigating environmental exposures that may drive or exacerbate the condition.

In an ongoing project, she and her collaborators are combining clinical and residential data with spatial data on air pollution in the Pittsburgh region to examine links between chronic rhinosinusitis and exposure to pollutants, such as black carbon and fine particulate matter (PM 2.5). These efforts have already resulted in several published papers showing connections between the disease and certain pollutants.

“Many of my patients also are exposed to fumes and dust in their jobs at factories, hydraulic fracturing operations, hair salons, restaurants, or other workplaces,” says Dr. Lee. “It’s hard to prove a causal connection, and much more research is needed, but we are seeing associations between chronic rhinosinusitis and poor workplace air quality.”

Breakthroughs in Cystic Fibrosis Research

Patients’ microbiomes also may play an important role in driving or exacerbating chronic rhinosinusitis. Currently, Dr. Lee is studying connections between the microbiome and chronic rhinosinusitis in patients with cystic fibrosis. “This form of the disease does not have that type-2 inflammatory connection, but these patients do have polyps and they suffer tremendously,” she says.

For this project, she is collaborating with Jennifer Bomberger, PhD, from the Department of Immunology at the University of Pittsburgh, to examine how the microbiomes of patients with cystic fibrosis evolve over time, and how those changes correlate with viral infections and nasal polyps. “We’re using a variety of advanced techniques, incorporating machine learning, genome sequencing, and proteomics, and hopefully our findings will eventually translate to improved clinical care,” says Dr. Lee. “Now with advanced therapeutics such as TRIKAFTA™ (elexacaftor/tezacaftor/ivacaftor and ivacaftor) we have a multi-institutional grant to study smell, microbiome, lung function, radiographic, and quality-of-life outcomes measures in patients with cystic fibrosis before and after starting the therapeutic. This study will help us better understand the inflammatory, functional, and microbial abnormalities in the disease process in relation to clinical measures and, hopefully, how recovery occurs.”

A Device for Objectively Assessing a Patient’s Sense of Smell

Dr. Lee also is using advanced technologies to develop new, more precise ways to monitor symptoms of chronic rhinosinusitis and other sinus conditions. Specifically, she is developing an “olfactometer,” a device for assessing a patient’s sense of smell much more objectively than is possible with current clinical methods.

The olfactometer delivers different odors to a patient’s nose in a highly quantifiable, programmable manner. Meanwhile, the patient’s brain activity is measured via magnetoencephalography (MEG). Dr. Lee says the sense-assessing technology is now at a patentable stage.

“Smell is often taken for granted, but it can be devastating not to be able to taste your food, and it is dangerous not to be able to smell smoke from a fire or spoiled food,” says Dr. Lee. “With the olfactometer, we can hopefully deepen our understanding of loss of smell and develop better ways to diagnose it, first of all, and then treat it, too.”

Reflecting on the scope of her research, Dr. Lee identifies collaboration as a powerful underlying theme. Because of its translational nature, her work depends on partnerships with scientific collaborators like Dr. Bomberger and clinical collaborators from other fields, like Dr. Wenzel.

“For me, basic to translational research is not only a means to bring mechanistic findings to solve clinical problems but the reverse is true and important. It is an ongoing cycle in which clinical research informs basic science, and that interaction is very exciting and could not be possible without collaboration,” she says.

References

1 Ahmed OH, Moore JA, Bruno R, Velazquez N, Poplawsky AJ, Lavigne P, Gardner PA, Lee SE. Neuromapping Olfactory Stimulation Using Encephalography (Nose) — A Proof of Concept Study. Abstract. Presented at Rhinoworld 2019, Chicago, 2019.
2 Ahmed OH, Moore JA, Bruno R, Velazquez N, Poplawsky AJ, Lavigne P, Gardner PA, Lee SE. Neuromapping Olfactory Stimulation Using Encephalography (Nose) — A Proof of
Concept Study. 
3 Li Z, Zeng M, Deng Y, Zhao J, Zhou X, Trudeau JB, Goldschmidt E, Moore JA, Chu H, Zhang W, Yin S, Liu Z, Di P, Lee SE, Wenzel SE. 15-Lipoxygenase 1 in Nasal Polyps Promotes CCL26/eotaxin 3 Expression Through Extracellular Signal-regulated Kinase Activation. J Allergy Clin Immunol. 2019 [in press].
4 Mady LJ, Schwarzbach HL, Moore JA, Boudreau RM, Willson TJ, Lee SE. Air Pollutants May Be Environmental Risk Factors in Chronic Rhinosinusitis Disease Progression. Int Forum Allergy Rhinol. 2018; 8: 377-384.
5 Olonisakin T, Moore JA, Wenzel S, Lee SE. Defining Endotypes Via Analysis of Cytokine Expression and Clinical Outcomes in Chronic Rhinosinusitis With Nasal Polyps. Abstract. Presented at Rhinoworld 2019, Chicago, June 2019.
6 Olonisakin T, Moore JA, Wenzel S, Lee SE. Defining Endotypes Via Analysis of Cytokine Expression and Clinical Outcomes in Chronic Rhinosinusitis With Nasal Polyps. In Press.
7 Velazquez N, Moore J, Mady L, Lee S. The Association of Air Pollutants, Airborne Occupational Exposures and CRS Disease Severity. Abstract. Presented at Rhinoworld 2019, Chicago, June 2019.