A Breath of Fresh Air in Cancer Treatment – An Inhalable Cancer Drug

Cells in the human body communicate constantly. One of the main ways they do so is by releasing tiny spheres called exosomes, carrying fats, proteins, and genetic material that help regulate everything from pregnancy and immune responses to heart health and kidney function.

The Emergence of Inhalable Cancer Drugs

Nature Nanotechnology published a new Columbia University study on 11 January 2024 showing that these 'nanobubbles' could deliver powerful immunotherapy directly to difficult-to-treat lung tumors through inhalation.

Study leader Ke Cheng, a professor of biomedical engineering, explains: 

"Exosomes work like text messages between cells, sending and receiving information. What makes this study important is that exosomes can deliver mRNA-based treatment locally to lung cancer cells, unlike systemic chemotherapy, which can cause side effects throughout the body. And inhalation is completely noninvasive. You do not need a nurse to pierce your skin with a needle for an infusion."

Cheng expects human trials to begin within 5 years. For now, the study is attracting attention because it signals progress in three areas of strong interest to both researchers and biotechnology companies:

• Therapeutic uses of exosomes
• Inhaled treatments for lung disorders
• Safe delivery of potent interleukin-12 (IL-12) immunotherapy

Study Details

Cheng and his laboratory team, who have developed exosome and stem cell therapies for more than 15 years, say they focused on lung cancer because it is often detected at more advanced stages.

“This disease has a high mortality rate. Treatments are inadequate and cause substantial damage to the organ.”

The team wanted to investigate new alternatives to systemic treatments. Most therapies are given intravenously, but Cheng believes exosomes—also called extracellular vesicles (EVs)—could change this. 

"One advantage of exosomes is that they are naturally secreted by the body or by cultured cells. Their toxicity is low, and they have several ways of delivering their messages to cells."

The scientists explored an approach that attracted public attention during the pandemic: Using messenger RNA (mRNA), which directs cells to produce proteins for tasks including boosting the immune response.

IL-12 has shown promise as a cancer treatment for years, but early human trials caused serious adverse effects and several deaths. Researchers are now testing new delivery methods that target tumor cells while having little effect on healthy tissue. Cheng's team took a new approach by placing mRNA for IL-12 inside exosomes. Another aim was to compare the effectiveness of inhaled exosomes and liposomes—engineered fat droplets also being investigated as drug carriers. 

The team's question was: "Which will work better at delivering IL-12 to the lungs to act against cancer without causing side effects?"

After laboratory mice inhaled the particles through their noses, the researchers observed that exosomes delivered more mRNA to cancer cells in the lungs and fought lung cancer with fewer side effects.

Three days after treatment, researchers saw cancer-fighting T cells flooding into the tumors, with higher levels following exosome-based treatment. Exosomes also led to the formation of more cancer-destroying natural killer cells (NKCs) and monocytes, indicating immune system activation.

The researchers also found that treatment acted like a vaccine, training the immune system to fight newly introduced cancers. Very little of the exosome-carried drug leaked into the blood, and the study produced minimal side effects. Cheng also said inhalation did not affect normal breathing.

Prof. Raghu Kalluri, chair of the Department of Cancer Biology at MD Anderson Cancer Center and an exosome researcher himself, said the use of inhaled exosomes made the study important. 

"This is an interesting study investigating inhaled delivery of engineered EVs to treat lung cancer, offering insights into focused delivery of EV-based drugs and implications for diseases beyond lung cancer."

New Possibilities Opened by the Study

Once regarded as  "a strange biological phenomenon"  or simply cellular waste, exosomes are now the subject of intensive medical research. Their potential includes carrying drugs, aiding wound healing, treating conditions ranging from pneumonia to heart attacks and intestinal disorders, and serving as measurable biomarkers that could lead to new cancer tests. An exosome-based prostate cancer test, the  ExoDx Prostate Test , is already on the market.

The surge in exosome research—from just a handful of published studies in the early 1980s to more than 9000 today—shows a particular focus on cancer. Annals of Oncology published a paper in 2021 reporting that clinical trials of exosomes for cancer testing and treatment far outnumber those for diabetes, heart disease, or neurological conditions. clinicaltrials.gov currently lists 52 clinical studies using exosomes in cancer diagnosis or treatment that have been completed, are ongoing, or are recruiting participants.

Cheng's approach could also be used to deliver other drugs to the lungs and other organs through inhalation. 

The team says it has tested inhalation for acute lung injury, a different type of lung condition.

Other potential targets include lung conditions such as pulmonary hypertension. Inhaled exosomes may reach the brain through the olfactory bulb or the heart, which receives oxygenated blood from the lungs.

Taking Medication by Inhalation

Remi Rosiere, a lecturer at Université libre de Bruxelles in Brussels, Belgium, and chief scientific officer of InhaTarget Therapeutics, which is developing its own inhaled treatments for severe respiratory diseases, says inhalable cancer treatments are not yet available outside research studies in the United States or Europe.

"Oncologists are very interested. If you concentrate the drug at the tumor site, you can prevent it from spreading throughout the body."

The first studies of inhaled chemotherapy began in the 1960s but failed because inhalation devices dispersed toxic cancer drugs into the air or delivered only small amounts to the lungs. New drug delivery techniques aim to change this. 

Rosiere's company is beginning human trials of a dry-powder inhaler containing the chemotherapy drug  cisplatin  for lung cancer. An immunotherapy treatment for lung cancer is also planned, packaged in lipid nanoparticles—small fat particles resembling liposomes.

Rosiere says Cheng's study also demonstrates the advantages of exosome delivery: "The data are quite convincing. Exosomes have a good safety profile and can remain in the lungs for a relatively long time. This extends drug exposure for greater effectiveness without causing toxicity.”

Moving from mice to human trials will take time. 

“You have to understand that this is a very early stage. There will be many challenges to overcome.”

One challenge is purely practical: he said that as the drug approaches human trials, regulators will ask whether exosomes can be manufactured in large quantities to meet the considerable demand for new lung cancer treatments.

A New Route for a "Powerful" Cancer Treatment

The Columbia University study showed that inhaled exosomes offer a unique delivery method for IL-12 and could help solve a major problem that has troubled this promising cancer treatment for decades.

In a 2022 literature review,  "one of the most powerful immunotherapy agents ever discovered" was the description given to  IL-12,  which caused severe side effects that halted research in the 1980s. New delivery methods are now reigniting the search. In 2022 and 2023, major pharmaceutical companies such as AstraZenca, Moderna, and Bristol Myers Squib reduced their involvement in IL-12 treatment research, leaving the field to smaller biotechnology companies developing delivery approaches that could make IL-12 safe and effective in humans.

These approaches include injecting the drug directly into tumors, coating it with various types of particles, masking it so that it becomes active only in cancer cells, and using IL-12 mRNA to turn tumor cells into factories producing IL-12.

Another IL-12 mRNA drug from Pittsburgh-based Krystal Biotech received fast-track designation from the United States FDA (Food and Drug Administration) in February 2024 for an inhaled lung cancer treatment that packages mRNA for IL-12 and IL-2 inside an engineered virus.

And, of course, there is Cheng's inhaled treatment, the result of decades of work in three developing fields.