Dupilumab, the generic form of Dupixent, is an effective treatment for moderate to severe asthma and multiple allergic conditions. Mount Sinai researcher Thomas Marron, MD, PhD, believes it also has the potential to shift the battle against non-small cell lung cancer, in the realm of both treatment and prevention.
Dr. Marron, Professor of Medicine (Hematology and Medical Oncology), and Immunology and Immunotherapy, at the Icahn School of Medicine at Mount Sinai, is collaborating with Mount Sinai pulmonology researchers on an observational study to test that theory among patients with eosinophilic chronic obstructive pulmonary disease (COPD), a subtype characterized by type 2 inflammation classically seen in allergic conditions and high levels of immune cells known as eosinophils. The Food and Drug Administration (FDA) recently approved dupilumab, a monoclonal antibody blocking interleukin-4 receptor-alpha (IL-4R⍺), to treat these patients. The researchers are looking at whether treatment with dupilumab to block IL-4 signaling—a key driver of type 2 inflammation—can reduce these patients’ risk of developing lung cancer in addition to improving their respiratory symptoms.
“We know that these patients with COPD are oftentimes current or former smokers, and are at high risk for developing lung cancer,” says Dr. Marron. “Although we screen these patients for early detection and intervention, we do not have treatment options for precancerous lesions beyond resection, which poses considerable risks. When the FDA announced dupilumab had been approved for treatment of eosinophilic COPD, we saw an opportunity to investigate whether this immunomodulating medication can reverse the growth of precancerous lesions.”
Dr. Marron’s interest stems from previous Mount Sinai studies showing that the immune cells that infiltrate lung cancers demonstrate characteristics of a type 2 immune response similar to those observed among patients with atopic diseases such as asthma or an allergic reaction. They subsequently found, in a study involving six patients, that they were able to reverse the growth of lung cancer in one case by combining dupilumab with immunotherapy. These findings were presented in a paper titled “An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis,” published in the December 6, 2023, edition of Nature.
The new study will recruit up to 20 patients with eosinophilic COPD from the Mount Sinai – National Jewish Health Respiratory Institute who have consented for longitudinal observational studies and who have agreed to receive dupilumab in addition to standard of care to manage their COPD symptoms. Eligibility for the therapeutic agent will be determined based on a diagnosis of COPD with elevated levels of eosinophils; only patients with a history of smoking and known pulmonary nodules on chest imaging will be followed.
“We specify that they should be on maximal inhaler therapy and experiencing ongoing respiratory issues, such as hospital visits for exacerbation of COPD,” says Jeremy Mudd, MD, Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) at the Icahn School of Medicine. “These are the types of cases that would warrant interventions with dupilumab."
A Mount Sinai research team is testing whether treatment with dupilumab to block IL-4 signaling can reduce the risk of developing lung cancer among patients with eosinophilic chronic obstructive pulmonary disease in addition to improving their respiratory symptoms. The team includes, from left, MD-PhD students Matthew Park and Ezekiel Olumuyide; Robert Samstein, MD, PhD; Dr. Mudd; and Dr. Marron.
Participants will be monitored through spirometry tests, clinically indicated computer-assisted tomography (CAT) scans, and blood tests conducted at intervals of two to four weeks, three months, and six months. Test results and scans from this cohort will be reviewed against those from a control group of eosinophilic COPD patients who are not receiving dupilumab.
Dr. Marron says the research team will be looking for changes in the functional status of the immune cells as a surrogate of what is happening in the tumor. They will also be looking at whether administering dupilumab disrupts age-related changes in systemic inflammation associated with cancer development, cardiovascular disease, and other medical conditions. But their main focus is whether administering dupilumab reverses the growth of precancerous pulmonary nodules.
“We know from screening that if lesions are there for more than a year, they may slowly grow, and eventually one or more may become cancer,” says Dr. Marron, who is also Director of the Early Phase Trial Unit at The Tisch Cancer Institute. “If we can get any nodules to regress, that will be exciting.” In those cases, he adds, patients will continue to receive dupilumab to treat their COPD as well as potentially control any remaining precancerous lesions.
Recruitment for the study is underway, as are plans for clinical trials of other immunomodulation therapies among COPD patients who are at high risk for cancer progression. Although the field of immune prevention is in its infancy, Robert Samstein, MD, PhD, a physician-scientist with a laboratory in Mount Sinai's Marc and Jennifer Lipschultz Precision Immunology Institute, is optimistic about its future.
“We are really good at lung cancer detection, and that is important,” says Dr. Samstein, who is also a radiation oncologist at Mount Sinai. “But what we want to achieve is a paradigm shift toward preventing cancer using the immune system. We are only one of a handful of centers looking into that possibility now, but it would not surprise me if, in 10 years, everyone is exploring immune prevention.”