OM DENNE EPISODE
Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. Andrew Lee, Vice President, Clinical Research at Uniquity Bio, about Thymic Stromal Lymphopoietin (TSLP) and eosinophilic esophagitis (EOE).
Disclaimer: The information provided in this podcast is designed to support, not replace, the relationship between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.
Key Takeaways:
[:49] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda. Ryan introduces co-host Holly Knotowicz.
[1:13] Holly introduces today's topic, Thymic Stromal Lymphopoietin (TSLP) and eosinophilic esophagitis (EOE), and today's guest, Dr. Andrew Lee, Vice President, Clinical Research at Uniquity Bio.
[1:36] Dr. Lee has nearly 20 years of experience in the clinical development of new vaccines, biologics, and drugs. Holly welcomes Dr. Lee.
[1:52] Dr. Lee trained in internal medicine and infectious diseases.
[1:58] Dr. Lee has been fascinated by the immune system and how it can protect people against infections, what happens when immunity is damaged, as in HIV and AIDS, and how to apply that knowledge to boost immunity with vaccines to prevent infections.
[2:16] Dr. Lee led the clinical development for a pediatric combination vaccine for infants and toddlers. It is approved in the U.S. and the EU.
[2:29] Dr. Lee led the Phase 3 Program for a monoclonal antibody to prevent RSV, a serious infection in infants. That antibody was approved in June 2025 for use in the U.S.
[2:44] In his current company, Dr. Lee leads research into approaches to counteract an overactive immune system. They're looking at anti-inflammatory approaches to diseases like asthma, EoE, and COPD.
[2:58] Dr. Lee directs the ongoing Phase 2 studies that they are running in those areas.
[3:28] Dr. Lee sees drug development as a chance to apply cutting-edge research to benefit people. He trained at Bellevue Hospital in New York City in the 1990s.
[3:40] When Dr. Lee started as an intern, there were dedicated ICU wards for AIDS patients because many of the sickest patients were dying of AIDS and its complications.
[3:52] Before the end of Dr. Lee's residency, they shut down those wards because the patients were on anti-retroviral medications and were doing so well that they were treated as outpatients. They didn't need dedicated ICUs for AIDS patients anymore.
[4:09] For Dr. Lee, that was a powerful example of how pharmaceutical research and drug regimen can impact patients' lives for the better by following the science. That's what drove Dr. Lee to go in the direction of research.
[4:48] Dr. Lee explains Thymic Stromal Lymphopoietin (TSLP). TSLP serves as an alarm signal for Type 2 or TH2 inflammation, a branch of the immune responses responsible for allergic responses and also immunity against parasites.
[5:17] When the cells that line the GI tract and the cells that line the airways in our lungs receive an insult or an injury, they get a danger signal, then they make TSLP.
[5:28] This signal activates other immune cells, like eosinophils and dendritic cells, which make other inflammatory signals or cytokines like IL-4, IL-13, and IL-5.
[5:47] That cascade leads to inflammation, which is designed to protect the body in response to the danger signal, but in some diseases, when there's continued exposure to allergens or irritants, that inflammation goes from being protective to being harmful.
[6:15] That continued inflammation, over the years, can lead to things like the thickened esophagus with EoE, or lungs that are less pliant and less able to expand, in respiratory diseases.
[6:48] Dr. Lee says he thinks of TSLP as being a master switch for this branch of immune responses. If you turn on TSLP, that turns on a lot of steps that lead to generating an allergic type of response.
[7:06] It's also the same type of immune response that can fight off parasite infections. It's the first step in a cascade of other steps generating that type of immune response.
[7:30] Dr. Lee says people have natural genetic variation in the genes that incur TSLP.
[7:38] Observational studies have found that some people with genetic variations that lead to higher levels of TSLP in their bodies had an increased risk for allergic inflammatory diseases like EoE, atopic dermatitis, and asthma.
[8:13] Studies like the one just mentioned point to TSLP being important for increased risk of developing atopic types of diseases like EoE and others. There's been some work done in the laboratory that shows that TSLP is important for activating eosinophils.
[8:38] There's accumulating evidence that TSLP activation leads to eosinophil activation, other immune cells, or white blood cells getting activated.
[9:07] Like a cascade, those cells turn on T-cells and B-cells, which are like vector cells. They lead to direct responses to fight off infections, in case that's the signal that leads to the turning on TSLP.
[9:48] Ryan refers to a paper published in the American Journal of Gastroenterology exploring the role of TSLP in an experimental mouse model of eosinophilic esophagitis. Ryan asks what the researchers were aiming to find.
[10:00] Dr. Lee says the researchers were looking at the genetic studies we talked about, the observational studies that are beginning to link more TSLP with more risk for EoE and those types of diseases.
[10:12] The other type of evidence that's accumulating is from in vitro (in glass) experiments or test tube experiments, where you take a couple of cells that you think are relevant to what's going on.
[10:28] For example, you could get some esophageal cells and a couple of immune cells, and put TSLP into the mix, and you see that TSLP leads to activation of those immune cells and that leads to some effects on the esophageal cells.
[10:42] Those are nice studies, but they're very simplified compared to what you can do in the body. These researchers were interested in extending those initial observations from other studies, but working in the more realistic situation of a mouse model.
[11:00] You have the whole body of the mouse being involved. You can explore what TSLP is doing and model a disease that closely mimics what's happening with EoE in humans.
[12:23] They recreated the situation of what seems to be happening in EoE in people. We haven't identified it specifically, but there's some sort of food allergen in patients with EoE that the immune system is set off by.
[12:55] What researchers are observing in this paper is that in these mice that were treated with oxazolone, there is inflammation in the esophagus, an increase in TSLP levels, and eosinophils going into the esophageal tissues.
[13:15] Dr. Lee says, that's one of the main ways we diagnose EoE; we take a biopsy of the esophagus and count how many eosinophils there are. Researchers saw similar findings. The eosinophil count in the esophageal tissues went way up in these mice.
[13:34] Researchers also saw other findings in these mice that are very similar to EoE in humans, such as the esophageal cells lining the esophagus proliferating. They even saw that new blood vessels were being created in that tissue that's getting inflamed.
[14:00] Dr. Lee thinks it's a very nice paper because it shows that correlation: Increase TSLP and you see these eosinophils going to the esophagus, and these changes that are very reminiscent of what we see in people with EoE.
[14:51] In this paper, the mice made the TSLP, and researchers were able to measure the TSLP in the esophageal tissue. The researchers didn't introduce TSLP into the mice. The mice made the TSLP in response to being repeatedly exposed to oxazolone.
[15:20] That's key to the importance of the laboratory work. The fact that the TSLP is made by the mice is important. It makes it a very realistic model for what we're seeing in people.
[15:41] In science, we like to see correlation. The researchers showed a nice correlation.
[15:46] When TSLP went up in these mice, and the mice were making more TSLP on their own, at the same time, they saw all these changes in the esophagus that look a lot like what EoE looks like in people.
[16:01] They saw the eosinophils coming into the esophagus. They saw the inflammation go up in the esophagus. What Dr. Lee liked about this paper is that they continued the story.
[16:15] The researchers took something that decreases TSLP levels, an antibody that binds to and blocks TSLP, and when they did that, they saw the TSLP levels come down to half the peak level.
[16:35] Then they saw improvement in the inflammation in the esophagus. They saw that the amount of eosinophils decreased, and the multiplication of the esophageal cells went down. The number of new blood vessels went down after the TSLP was reduced.
[16:53] Dr. Lee says, you see correlation. The second part is evidence for causation. When you take TSLP away, things get better. That gives us a lot of confidence that this is a real finding. It's not just observational. There is causation evidence here.
[18:26] Ryan asks if cutting TSLP also help reduce other immune response cells. Dr. Lee says TSLP is the master regulator for this Type 2 inflammation. It definitely touches and influences other cells besides eosinophils.
[18:44] TSLP affects dendritic cells, which are an important type of immune cell, like a coordinating cell that instructs other cells within the immune system what to do. In this paper, they looked at a lot of other effects of TSLP on the tissues of the body.
[19:10] Dr. Lee says, There's a lot of research on TSLP, and one of the reasons we're excited about the promise of TSLP is that it's so far upstream; so much of the beginning, that it's affecting other cells.
[19:29] Its effects could be quite broad. If we're able to successfully block TSLP, we could block a lot of different effects.
[19:40] One treatment for EoE is dupilumab, which blocks IL-4 and IL-13 specifically, and that works well, but TSLP has the potential to have an even greater effect than blocking IL-4 and IL-13, since it is one step before turning on IL-4 and IL-13.
[20:14] That's one of the reasons researchers are excited about the promise of blocking TSLP. There are studies ongoing of TSLP blockers in people with EoE.
[20:34] Ryan asks if there are negative repercussions from blocking TSLP. Dr. Lee says in this study and in people, we are not completely blocking TSLP by any means. There will still be residual TSLP activated, even with very potent drugs.
[21:01] In the study, they block TSLP about 50%‒60%. TSLP is involved in immunity against parasites. In studies with people, they make sure not to include anybody who has an active parasitic infection. A person under treatment should not be in a study.
[21:27] Dr. Lee says we haven't seen any problems with parasitic infections becoming more severe, but that is a theoretical possibility, so for that reason, in studies with TSLP blockers, we generally exclude patients with known parasitic infections.
[22:17] What excited Dr. Lee in this paper was that they showed that when you block TSLP in the mice, then you get real effects in their tissues. Eosinophils went away. The thickening of the basal layers in the esophagus got much better.
[22:38] That kind of real effect reflected in the tissue is super exciting to see. That gives us more confidence that this could work in people, since we're seeing it in a realistic whole-body model in the mice.
[23:12] Dr. Lee says there are ongoing clinical studies on TSLP blockers for EoE. His company is studying an antibody that blocks TSLP in eczema, COPD, and EoE. One of the exciting things about immunology is that it affects many different parts of the body.
[23:42] EoE is associated with other immune-type disorders. There's a high percentage of patients with EoE who have other diseases. EoE coexists with asthma, atopic dermatitis, and chronic rhinitis.
[24:09] It's exciting that if you figure out something that's promising for one disease that TSLP affects, it could have very broad-ranging implications for a variety of diseases.
[24:22] Ryan shares his experience of his doctor talking to him about a TSLP blocker, tezepelumab, as a potential option when it's out of clinical trials. It would target something a little higher up the chain and help with some of his remaining symptoms.
[24:59] Ryan is excited to hear that this research is so encouraging and how it could potentially help treat EoE, asthma, and other conditions, all at once.
[25:16] Dr. Lee says that being in these later-stage studies is super exciting. If these late-stage trials are successful, the next step is to apply for regulatory approval with the various agencies around the world.
[26:40] Dr. Lee shares one takeaway for listeners to remember. Think of TSLP as an alarm that turns on inflammation. He compares TSLP to turning on an alarm during a robbery. There are multiple steps designed to protect the bank and the money.
[27:20] To extend that analogy, with TSLP, once you turn it on, all these other steps are going to happen. Inflammation is designed to protect the body. It's a protective response. If there's an infection, it can clear the infection.
[27:38] If the infection persists, as in HIV, the immune response, which is protective and beneficial, eventually becomes damaging. It becomes dysfunctional. In EoE, if you continually eat the allergic food, the inflammation becomes damaging to the esophagus.
[28:27] Long-term inflammation leads to replacing the normal esophageal tissue with fibrotic tissue, and that's why the esophagus eventually gets hardened and less able to let the food go through.
[28:40] In respiratory diseases, the soft tissue of the lung gets replaced with thicker tissue, and the lung is not able to expand.
[28:54] Dr. Lee says he people to think about TSLP as this master alarm switch. We hope that if you could turn off that TSLP, you could then avoid a lot of the complications that we see with chronic inflammation in these conditions.
[29:14] We're hopeful that you could even take away the symptoms that you see in these diseases, make patients feel better, and with extended treatment, you could begin to reverse some of the damage resulting from inflammation.
[29:32] Ryan likes that analogy and how Dr. Lee has concisely explained these complicated concepts.
[29:51] Dr. Lee thanks Holly and Ryan and adds one more plea to listeners. Please consider getting involved with research. Clinical trials cannot be done without patients. We need patients to advance new treatments.
[30:27] Researchers like Dr. Lee spend a lot of time thinking about how to make the studies not only informative but also fair to patients who decide to become involved. It's a lot of work and a fair amount of time commitment.
[30:44] If you don't want to be in a study, you can help by being on a patient feedback panel and reviewing protocols and informed consents. Follow your interests. Think about getting involved with research, however you can.
[31:06] Ryan and Holly are very grateful for the community, with so many wonderful clinicians and researchers, and so many patients who are willing to volunteer their time and their data to help researchers find better solutions going forward.
[31:26] Ryan thanks Dr. Lee for coming on and putting out that call to action. It's a great reminder for listeners and the patients in the community to look for those opportunities. Chat with your physician. Go to APFED's website. There's a link to active clinical trials.
[31:47] For our listeners who want to learn more about eosinophilic disorders, we encourage you to visit apfed.org and check out the links in the show notes below.
[31:53] For those looking to find specialists who treat eosinophilic disorders, we encourage you to use APFED's Specialist Finder at apfed.org/specialist.
[32:01] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at apfed.org/connections.
[32:11] Ryan thanks Dr. Andrew Lee for joining us today. We learned a lot. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda for supporting this episode.
Mentioned in This Episode:
Andrew Lee, M.D., VP Clinical Research, Uniquity Bio
"A Mouse Model for Eosinophilic Esophagitis (EoE)" Current Protocols, Wiley Online Library
APFED on YouTube, Twitter, Facebook, Pinterest, Instagram
Real Talk: Eosinophilic Diseases Podcast
apfed.org/research/clinical-trials
Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda.
Tweetables:
"I see drug development as a chance to apply cutting-edge research to benefit people." — Andrew Lee, M.D.
"When the cells that line the GI tract and the cells that line the airways in our lungs receive an insult or an injury, they get a danger signal, then they make TSLP." — Andrew Lee, M.D.
"Observational studies have found that some people with genetic variations that lead to higher levels of TSLP in their bodies had an increased risk for allergic inflammatory diseases like EoE, atopic dermatitis, and asthma." — Andrew Lee, M.D.
"There's a lot of research on TSLP, and one of the reasons we're excited about the promise of TSLP is that it's so far upstream; so much of the beginning, that it's affecting other cells." — Andrew Lee, M.D.
"Please consider getting involved with research. We can't do these clinical trials without patients. We need patients to advance new treatments for patients." — Andrew Lee, M.D.
