Researchers evaluate lung cancer treatment that can be inhaled
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Researchers at Columbia University's Herbert Irving Comprehensive Cancer Center are investigating a lung cancer treatment that can be delivered directly to the lungs.
The treatment, which involves the inhalation of interleukin-12 (IL-12) messenger RNA, uses nanobubbles to facilitate local delivery to the lungs with fewer off-target side effects.
Results of a preclinical study, published in Nature Nanotechnology, showed the approach has the ability to shrink tumors and prevent recurrence of lung carcinoma in mice.
Ke Cheng, PhD, professor of biomedical engineering at Columbia, and Brian S. Henick, MD, a medical oncologist at Columbia specializing in malignancies of the upper-aerodigestive tract, are developing the noninvasive approach.
“As an engineer, you always want to solve problems. In this area of drug delivery, the challenge is how much drug you can get to the right organ versus how much is lost off target,” Cheng told Healio. “If these drugs hit the healthy cells of the body, you have toxicity. So, for lung cancer, we would intuitively think that inhalation would be a method of local delivery to the lung.”
Healio spoke with Cheng and Henick about how they are developing this approach, how it has performed so far, and the next steps in research.
Healio: Can you describe this novel approach and how it works?
Cheng: This drug is an mRNA, which provides the blueprint to make proteins. Once you have the blueprint, you are utilizing your body’s own cells to produce that protein. This protein is called interleukin-12, and we are not the first to use it. It is integral for anticancer therapy and has been used in several trials with mixed results. IL-12 is a cytokine, which recruits immune cells to attack cancer cells.
Healio: How is this delivery method different or safer than drug delivery through the bloodstream?
Henick: One major problem we see in medical oncology is that we systemically administer drugs through the bloodstream, like chemotherapy and immunotherapy. Although these drugs might have the desired impact on the target, the wide distribution of these medications can cause side effects throughout the body. This is one reason we are limited in the doses we might be able to give in terms of chemotherapy. For immunotherapy, the drugs work a bit differently in that immune checkpoint inhibitors allow immune cells throughout the body to be activated, ideally against the cancer. However, these can also cause side effects against any organ in the body. The concept of being able to locally deliver a therapeutic is appealing.
As Dr. Cheng mentioned, it can be challenging to directly administer a drug to cancers in the lung. Often you must utilize a needle and go through the skin and other layers of the lung lining to get to the cancer. Similarly, if you go by the airway, you have to traverse critical structures to get there. There are many complications that can arise just from the procedure of administering a local drug, so it’s not usually feasible to directly administer cancer drugs to the lungs. The prospect of being able to achieve local delivery to the lungs through an easy-to-administer process is very appealing. It might limit some of the side effects that we see from the distribution of the drug to off-target locations. The prospect of having a local immune response that’s driven by a drug that gets administered in the tumor microenvironment, and some of the locally responsive immune cells, may be a more organic way to achieve system-wide control of the cancer. That’s something we won’t know for certain until we are able to do trials. However, it is a theoretical benefit to this type of delivery.
Healio: How would a patient take this drug?
Cheng: This is taken through a nebulizer. The patient puts the drug solution into a bottle, and a machine creates very tiny droplets that the patient can inhale. This isn’t the most convenient way; the most convenient way is a pocket-sized dry powder inhaler. In this approach, the drug is turned from a liquid into a powder, and you can just squeeze [the bottle] and it goes in. This will be the next-generation delivery. In this paper, we are still using the liquid nebulization. However, dry powder innovation is a goal for the future.
Healio: How has this approach performed so far in your research?
Cheng: The present study was a proof-of-concept small-animal model looking at the efficacy and safety of this approach. We did see efficacy in terms of killing the tumor cells and prolonging longevity in these mice. We also saw safety, meaning that this drug did not cause toxicity in these mice. This is encouraging, although it is preliminary.
Healio: What are your next steps in research?
Henick: Even though this work was conducted in mice from the standpoint of the delivery system, Dr. Cheng has founded a company that is conducting trials in patients with interstitial lung disease and is studying the administration of other types of exosomes. Exosomes have already entered the clinical space and are being investigated for different purposes. Some existing products are approved for clinical trials in patients with acute respiratory distress syndrome. If a similar product has been approved for testing in humans, we’d just need to prove to the FDA that with a bit of modification, it could be used for a different indication like lung cancer. We want to make a very cautious statement that one thing can be applied to the other.
Healio: What are the potential implications of your findings?
Henick: This gets to two fundamental questions in medical oncology. On the one hand, there’s antitumor efficacy. We’re trying to help shrink tumors and help patients live longer. We know some patients experience very good results with existing drugs, but many patients either don’t respond to treatment or initially benefit and then lose that benefit. One of the pressing needs is to help patients who are not benefitting do better. We hope this system will deliver a drug that is effective against the cancer in patients whose treatment isn’t working.
The flip side is whether we are achieving this benefit at the expense of side effects. Are we causing system-wide side effects that make it impossible to deliver that medicine to the patient? Optimizing these two factors is called the therapeutic index. What dose of which medicine do we need to get to achieve the most benefit without causing toxicity? This delivery system seems as though it should be highly feasible, easy for patients to use, and ideally will deliver the drug to the most relevant area without side effects.
Although this paper focused on the study of the mRNA construct for interleukin-12, it can be used with any other drug and any other relevant immune target. Other relevant cytokines are being developed for the treatment of cancer and are showing efficacy in patients. The ability to use this platform not only with this particular cytokine but with other drugs that may be relevant and even more effective is very appealing. As we consider how best to get from mice to people, these are the kinds of factors we’ll have to weigh. However, the delivery system seems very feasible in the earliest models.
Reference:
For more information:
Ke Cheng, PhD, can be reached at ke.cheng@columbia.edu.
Brian S. Henick, MD, can be reached at bh2682@cumc.columbia.edu.
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