Immune Tolerance Development and the Benefits of Early Introduction

The LEAP trial fundamentally changed our understanding of immune tolerance, demonstrating that early oral exposure can dramatically reduce the risk of developing peanut allergy. In this episode, Edwin Kim, MD, FAAAAI, will help us explore the immunologic mechanisms of early food introduction and tolerance development and what the evidence tells us about other food allergies.

Transcript

Rebecca Saff, MD, PhD, FAAAAI 0:10

Hello and welcome to Conversations from the World of Allergy, the podcast of the American Academy of Allergy, Asthma & Immunology. I'm your host, Dr. Rebecca Saff. Allergy and Immunology is a field that's evolving at an incredible pace, and staying current isn't just important, it's essential. This podcast brings you conversations with leading experts to explore the latest advances, challenge how we think about core topics, and ultimately help us deliver the best care to our patients. For decades, parents were advised to delay introducing allergenic foods, particularly peanuts, to infants. The LEEP trial and others fundamentally changed our understanding of immune tolerance, demonstrating that early exposure can dramatically reduce the risk of developing allergy. In this episode, we'll explore the immunologic mechanisms of early food introduction and tolerance development and what the evidence tells us about other food allergies. We'll also talk about how clinicians can help families successfully implement these recommendations in everyday practice to continue to decrease food allergies in kids. Today we welcome Dr. Edwin Kim. Dr. Kim is a physician scientist in pediatric allergy and immunology and the division chief of pediatric allergy and immunology at University of North Carolina. He is the director of the UNC Food Allergy Initiative, which investigates the basis of food allergies as well as forms of immunotherapy is treatment. Dr. Kim's research group focuses on safety and tolerability of immunotherapy and the underlying mechanisms involved in successful treatment. I'm so excited to talk to him about how early introduction has changed our thinking about tolerance development. Dr. Kim, thank you so much for taking the time to join us today. Welcome to the podcast.

Edwin Kim, MD, FAAAAI 1:38

Yeah, super excited to be here.

Rebecca Saff, MD, PhD, FAAAAI 1:40

I'd like to start by getting to know you a little bit better. Can you tell me a little bit about yourself and how you got excited about allergy immunology?

Edwin Kim, MD, FAAAAI 1:47

Yeah. So um again, my name is Edwin Kim, and I uh was born at Mount Sinai Hospital in New York and then spent most of my growing up in New Jersey. Ultimately ended up going to Rutgers Medical School, and then I've done my pediatric training as well as allergy here in North Carolina, where I am right now. Uh residency and fellowship at Duke, and now faculty at the University of North Carolina since 2011. So yeah, thinking about, you know, I think in planning for this, I was really trying to remind myself of you know what gets me excited about allergy and immunology. How did I get into here? And honestly, I think it just goes back to um basic immunology. And so I was always really fascinated with this kind of early concept of your immune system, there's one antibody for every bad thing that could potentially be out there and it protects us. Um and so I was like, oh wow, that's pretty cool. But then starting to really learn about things like allergy and autoimmunity. Okay, the immune system is supposed to be so perfect, but then it's not. So why is it overreacting to things? Why is it having hypersensitivity that leads to allergy? Why is it attacking itself for autoimmunity? And I think that's really what got me interested in sort of the field as a whole was sort of uh first this idea of the perfect immune system, but then how many different ways that it can sort of not work. Clinically, though, the other thing that comes to mind is my gosh, everybody knows somebody with allergy, whether it's seasonal allergies, whether it's food allergy, whether it's you know asthma. And so I do think that the potential that we can help is so, so, so huge. Um, it affects so many people that are out there. So I think at the science level, but also at the clinical level, uh, two things that have really driven me and excite me about being in uh the allergy world and food allergy in particular, I think it's just so front and center on everybody. I mean, everything we do seems to center around eating and food and happy hours or whatever else I might be. And so again, I think just such an opportunity where, you know, uh so much we don't know, but also an opportunity where we can make a huge difference.

Rebecca Saff, MD, PhD, FAAAAI 3:41

Yeah. And one of the exciting parts about allergy immunology is how much our what we know has changed over the years. And so um, I wanted to start by talking about how we think about early introduction of foods and how the recommendations have changed over kind of the course of the last 20 years. Can you maybe talk us through kind of what we knew and now where we are?

Edwin Kim, MD, FAAAAI 4:00

Yeah. So actually, as it turns out, my training sort of overlapped right through this whole whole period. And so um, there was sort of a time where, you know, again, we like you said, we diagnose an allergy and then we strictly avoid it. We don't want to challenge the immune system. We want to give the immune system sort of an opportunity to uh try to mature itself and tolerate the food. Um and uh, but then, you know, in the middle of my training is when we took away those guidelines about um about sort of when to eat the food. And so we were sort of there was a period of time where we just weren't sure. Like, do you give the food, do you not? Do you wait till they're older? Um, and so that was a really, really difficult period, I think, from from uh clinical practice as far as what do we tell our patients, but also you know, what parents were trying to understand. But now, you know, I think getting to the point where we are understanding that there is a window of opportunity, the immune system, there is a time where the immune system is more likely to become tolerant to all manner of things, including food. And so it just makes sense to me. But it has been crazy that over 10, 15 years to sort of see this complete 180, uh, going from uh strictly avoiding it, waiting, waiting longer and longer to introduce the food to now like get it in there as fast as possible and really take advantage of the immune system, as opposed to the immune system being somehow uh something that's set up to do something bad.

Rebecca Saff, MD, PhD, FAAAAI 5:14

And one of the things that really was kind of a frame shift is the sleep trial. What do you think about it made it so impactful at the time?

Edwin Kim, MD, FAAAAI 5:23

Yeah, I mean, again, it was the biggest difference was it was opposite, right? So up to that point, even us as allergists, I think if you said one, two, three, we all knew what that meant. And that was like wait till age one for milk, age two for egg, and age three for peanut. And um, you know, we did it wasn't based on a lot of evidence that was out there, but that was something that we were just all trained under. We knew that. And then suddenly to sort of see this study that says, oh no, we're gonna do the opposite, and we're gonna give peanut as early as four to six months was like, oh my gosh. And on the one hand, like I could convince myself from the immune system point of view, yeah, let's do this, it makes sense. But then there's that part of you that says, well, clinically we've not done this. And what if a six-month-old gets sick, has anaphylaxis? And so it was definitely a struggle that I'm guessing that many other allergists had had. Um, but uh, but such an important study to be done to really test that question and see.

Rebecca Saff, MD, PhD, FAAAAI 6:15

And so why is that that time frame, that you know, kind of four to eleven months that the LEAP trial kind of focused on, why is that such an important time for tolerance? What's going on in the infant?

Edwin Kim, MD, FAAAAI 6:26

Yeah, so I think they're like um we talk a lot about oral tolerance, right? And so one of the ways I talk to uh fellows, uh colleagues, but also to my patients is the idea that everything we eat is foreign to us, right? So we focus on, say, peanut and milk, but if you think about it, everything you have for breakfast, lunch, dinner, none of those things are naturally part of our bodies. But clearly our body is not reacting to all those other things. And so uh I use that to just kind of remind folks that our our means, our GI tract is designed to not be allergic, uh, this concept of oral tolerance. And so, what do we think is happening uh in people becoming allergic is uh what we're worried about is that if you get exposed to those food allergens by some other means as opposed to the oral tolerance. So if you get exposed to, say, peanut through the skin, if you get exposed to peanut through breathing it in, uh your immune system sees it in those in those settings uh that are not necessarily designed to uh to set up tolerance. And so it's almost like a race against time. Can you get it into the system? Can you get it into the GI tract where you normally would develop tolerance prior to getting exposed in these other ways that maybe will set you up to become allergic?

Rebecca Saff, MD, PhD, FAAAAI 7:32

And then what about eczema? Makes kids so much more likely to develop, to not to develop tolerance.

Edwin Kim, MD, FAAAAI 7:38

Yeah, exactly. And so that's of course, that's probably if there's any risk factor out there that we think of for food allergy, eczema is going to be the one we're most worried about. And it goes right back to that same kind of concept. So we're trying to actually get it into the GI tract before they can get exposed. Uh, and one of the things that increases that risk of exposure is going to be eczema. So if you've got your skin is supposed to be that perfect barrier, keep all the yucky stuff out. But if you've got eczema and hard to treat eczema, that skin barrier is just not functioning the way it needs to. And so uh it makes sense that it increases the likelihood that you're going to get those food allergens through the through that broken barrier to the immune system uh setting up for allergy.

Rebecca Saff, MD, PhD, FAAAAI 8:17

And then we know more and more about the skin barrier that it's not just kind of having active inflammation, that that skin is actually even at baseline, when it looks normal, there's something different about it in terms of how it is a barrier to the outside. Um, what about the immune system kind of does that? What why is it even having that barrier kind of disrupted makes such a difference?

Edwin Kim, MD, FAAAAI 8:39

Yeah, so I mean, I think there's still a lot of work we're trying to do, of course, to try to truly understand this. I think the one of the models we think about is this phalagrin mutation, right? So we have some patients who have a certain mutation that really exaggerates sort of the that the skin barrier dysfunction and the pro sort of uh allergic kind of uh milieu that's there. Um, but we do know exactly, as you say, that even in cases with mild eczema, like if you actually are look able to look at the skin underneath, you're going to see that again, uh, there is a barrier defect that's there, even if it's not sort of apparent. Um, but then also again, it just seems to be that some patients are more prone to sort of this TH2, this more uh kind of allergic inflammatory response as opposed to the more TH1 kind of um, you know, fighting off infection type of type of response as well. And so we've tried to use that as far as thinking about what are interventions we can do. So, yes, there's the try to feed the food early, but are there things we can do to the skin? Are there things we can do to the immune system? So at the skin level, can we improve that barrier? Uh can we get emollience on early on? Can we uh reverse sort of eczema before it gets bad? Uh, but also some of these biologics trying to sort of shift that immune system away from TH2 and more towards TH1, and can that sort of also help us to um sort of set up the right environment that we're not likely to become allergy?

Rebecca Saff, MD, PhD, FAAAAI 9:58

And are there markers that we're seeing that really help to us to understand tolerance as these kids, you know, these kids that are not introduced versus now are introduced, their IgE or their IgG4, or there are there markers that we are starting to look at in terms of tolerance?

Edwin Kim, MD, FAAAAI 10:13

Uh if you can tell me what that is, I would love it. I mean, I think I do think that the by the diagnostic biomarkers are uh an area of huge, huge, huge need for us. And um I think what we have seen sort of at baseline, but also on treatment on the different treatments we've done is sort of globally at a cohort level, we can make some statements. So yeah, IgE is bad. And so high IgE clearly is suggesting you're likely to have a reaction. Um, IgG seems to be a protective kind of antibody. And so if you have some at baseline or if you can develop some on treatment, it does seem to protect against um allergy or at least increase your threshold. Uh, but then the problem ends up in clinic at the single patient level, uh, that sort of doesn't hold true. Uh we don't have the great cutoffs there as well. And so um I'll use peanut as an example. So skin tests of five millimeters in one kid versus another maybe two completely different things. And so we are, you know, looking for different markers around IgE. So again, like your uh food-specific IgE, we are looking at components uh uh IgE to different components of peanut. Um we're looking at functional tests, we're looking at the basophil activation test, the mast cell activation test to try to see sort of uh in vitro whether we can we can see reactivity. So we we continue to look at this, but unfortunately, right now we have a lot of good biomarkers, but no great biomarkers at the moment.

Rebecca Saff, MD, PhD, FAAAAI 11:33

Yeah. And as you said, I think that on a patient level, we just don't know enough to use that as predictive versus kind of what we know at a population level is true. So you can you can you can't extrapolate to the individual yet, but hopefully over time we'll start to have more of those things.

Edwin Kim, MD, FAAAAI 11:49

Yep, absolutely. Yeah. And so I mean, just one other quick comment there is you know, back to this idea of early introduction and trying to prevent allergy. Uh, if anything, I think some of that screening testing um does sort of set a timeline for us. If you've got that person who's got negative testing, okay, great, let's get this going. If you've got someone who's got a low positive, though, that's one of those get them in as fast as possible because it's almost like even more of a that race against the clock. Uh, before their immune system has that opportunity to become sort of full-blown allergic, uh, can we get that food in there and actually sort of make sure that it never gets to that point? Um, and so uh again, we need better biomarkers. Um, but you know, what we have is okay, and we're doing the best that we can with what we have right now.

Rebecca Saff, MD, PhD, FAAAAI 12:28

And then say we introduce it at four to eleven months, we get some tolerance, that's great. How durable is that? If you then didn't eat it forever, how likely are you to go on to then develop allergy versus not? And is the duration important? Is the amount you eat? What do we know?

Edwin Kim, MD, FAAAAI 12:45

These are all like all the questions that we're dealing with on a daily basis. And so, first of all, I'm just gonna call out George Du Toit and Gideon Lack and just the amazing, amazing work that this leap team did. Because um, you know, they followed these kids all the way out till age five for the leap study itself. And so, just again, the idea that you know you you're getting these kids at four months and now you're treating them and following them for five years, is that's hard enough. Uh, but then what their group was able to do was to you know to try to answer your question, the durability part, they did that leap-on study. And so at at age five years, uh, after they did their assessment of whether allergic or not, then they took the peanut away. So no more of this sort of regular exposure to peanut for a year to try to get at this durability thing. And so uh, you know, when you take it away for a year, do all those people who are not allergic suddenly flip to become allergic? And thankfully, the the uh result looked like that was not the case. And so a couple people became allergic in the treatment group, but a couple people in the avoidance group did as well, so equal amounts. So seemingly demonstrating a level of durability, at least for that one year. Um, but then they continued, and so then they did the leap try the leap trio study. So they followed these kids all the way out to age 13, which again is just incredible to imagine that you can have this cohort of kids. Um, and really speaks to sort of the um just how dedicated this team was. And so they followed them out to age 13. And between age six and 13, they kind of let the these kids eat whatever they want to do, sort of this ad lib concept, and then checked again to see who flipped and became allergic. And it does look like it's been just uh it's been fully durable. And so I do think that we can make that difference. Uh, it's not sort of a temporary treatment that I think we're doing by introducing it early. I think we are actually keeping them from becoming allergic. Um, but you know, your second part of the question is something that we are struggling with right now that we know in the study it worked, and with their magical team it worked, but what uh but implementation is hard. And so, you know, how frequently and how much I think are questions that we are trying to answer. And right now, uh, because we've seen it in the study, we're trying to do what they did in the study. So, can we get at least two grams of peanut in there a couple times a week? But easier said than done for some families, I think. And so I do think it is something that uh in clinical practice and also in research, the more we can try to understand what is that sort of minimum amount, or you know, it's uh the frequency as well as the amount, I think is going to be an important piece that we're trying to understand. Um, as well as the do we need to go out to age five? Um, because it's hard, right? It's hard being a parent. Uh and then when we add stuff like this on top of that, it makes it difficult. And so um, you know, in clinic, I do try to try to you know show a level of sort of understanding around that too, of like, hey, this is what we're trying to do, um, but not sort of to the point where we're guilting families, right? Because that's the one thing we don't want to do. Again, it's I mentioned a second ago, but it's hard to be a parent, right? And so as much as they can do, and as long as they can kind of keep it going is I think more of a realistic way to go. If they can get out to five years, amazing. Um, but we don't know for sure that you have to do that. Maybe three or age, three or four is good enough. And so, really, the idea of like, you know, can get it in there as consistently as you can and let's get just go for it as long as you can. And if you can't, you can't, we'll talk through it, we'll come up with a strategy at that point.

Rebecca Saff, MD, PhD, FAAAAI 15:58

I mean, the the leap trial had just this amazing rate of retention as well. Like they were really able to keep these kids in this trial for so long. So, you know, kudos to them. What an amazing effort to really be able to keep those kids engaged and the parents engaged.

Edwin Kim, MD, FAAAAI 16:13

Yeah.

Rebecca Saff, MD, PhD, FAAAAI 16:14

And we've been talking about peanut, and you kind of talk about how hard it is even just to keep peanut in the diet on a regular basis. What do we know about all the other allergenic foods, tree nuts and sesame and egg and milk? Um, what do we know about early introduction of those? And is it more extrapolated at this point, or do we have start to have more data on what we need to do for different foods?

Edwin Kim, MD, FAAAAI 16:34

Yeah, they are their same group tried to do what they call the eat study. And so they did try to kind of look it across those, you know, top nine allergens as well, so broadly beyond peanut. Um, and I think the the first thing I would say is that's a way hard. I mean, it's easy to see how that's a way harder study to do. Um, and so that study uh didn't quite have the outcome that they'd looked for. So they did replicate the peanut, uh the peanut uh result. It seemed to be a suggestion that egg, early introduction to egg could be protective as well. They didn't quite show that for the other foods, but uh I think it had a lot more to do with sort of the difficulty of the study and the study design than the actual concept itself. Because it just makes sense if you step back and think about how oral tolerance works and you know, why we think peanut works. Uh, why wouldn't that be the case for the other foods? And so um, really the way I think about it right now in clinical practice is like there's no benefit to delaying. You know, I mean, I like way back we used to say, okay, wait till H3. Clearly we know that's wrong now. Um, but there's really no benefit to waiting. But I think there could be very likely a tremendous benefit to trying to get it in there early as well. Can I say that it's data proven that like getting sesame in at four months will work? No, but I think everything points towards that should be the case, uh, from what we understand from it. So that's really the way I try to talk to our patients about it is like you try to get it in there, uh, it just makes sense. Um, uh, it works for peanut and everything says it should work for the other foods as well.

Rebecca Saff, MD, PhD, FAAAAI 17:57

Yeah, the calendar that they had for how parents were supposed to give food. Oh my goodness. Um, as the parent of four children, I'm just trying to imagine my third child and being like, I give up. Like I can barely brush people's teeth, like, let alone try to get exactly shellfish in on two days and sesame. It's just incredible effort on everyone's part.

Edwin Kim, MD, FAAAAI 18:16

Yeah. But that, you know, that does bring up sort of the question of like, clearly, our parents and their parents, um, we didn't have to plan out all this, you know, feeding. It's still so it still goes back to the idea of like, how do we get here? You know, and what has changed sort of in the environment, what has changed genetically that has sort of set this up that now we are having to reverse out of this. And so clearly still lots and lots of work to do. Um, but at least we have something that we can do actively now while we're still trying to discover that, you know, what happened and why are there so much more allergies? So there is some stuff that we can do to try to help these families and try to prevent as much of the allergy as possible.

Rebecca Saff, MD, PhD, FAAAAI 18:52

Um, what are your favorite theories as to why this has become such a problem? Do you think it has to do with how we prepare the food? Uh, you know, there's the hygiene hypothesis, sunlight, and vitamin D. Do you have like your favorites of those or all of them?

Edwin Kim, MD, FAAAAI 19:06

Yeah. Yeah, I get, I think it's a little obviously like you can always punch holes in every one of these theories, right? And so there's always an exception to each of these. Um, it still seems to make a lot of sense that this sort of global hygiene hypothesis kind of idea that like our immune systems sort of skew one way or the other. And so again, trying to get exposed immune system sort of at that right window of opportunity. And it kind of that also ties in with this dual hygiene hypothesis, the skin, you know, skin and respiratory exposure versus oral. But it yeah, I do still sort of fall back on that uh to sort of set some patients up. So, you know, I am concerned about the heavy use of antibiotics that we have sort of super duper early on and what impact that has on our gut microbiome and the developing immune system, and then sort of adding foods on top of that. Um, a lot of these processed foods. I mean, again, so many of these theories, I think there's bits and pieces of all of them that are likely true, it would be my guess. That are the crops different? The crops are probably different too, right? I mean, is it a malicious sort of conspiracy? Of course not. Um, but we there's a lot more people we need to feed, and so there's probably that changes that are happening there. So I can't, as much as I wish and hope there's a silver bullet, there's no way there's a silver bullet here. I think it's probably a constellation of things. There's genetics that sets patients up for this, and then these different exposures that are happening, and the timing of these exposures, I think, is is critical here.

Rebecca Saff, MD, PhD, FAAAAI 20:27

Do you think that this is all completely allergen specific? Or do you think that getting multiple foods in early gives you kind of more broad protection against allergy?

Edwin Kim, MD, FAAAAI 20:38

Yeah, I I want to believe that, but it feels like right now in clinical practice that it's allergen-specific. I I wish, wish, wish that there was we could kind of say, oh, we've sort of turned on the protective part of the immune system across just foods. But um, at least right now, I feel like in clinic, what we're seeing is probably more allergen-specific, unfortunately, which goes back to the oh my gosh, gosh, this is hard. How do you get nine foods into the like on a daily basis when you can't get your kids to even brush their teeth and stuff?

Rebecca Saff, MD, PhD, FAAAAI 21:04

Maybe that's just my problem. That was always like the brain.

Edwin Kim, MD, FAAAAI 21:07

Same in our house. I mean, we've got the three kids in our house, and um, you know, I I will bring up here again back to the implementation. And this is a place where even when we, you know, feel like we have confidence in the science, there's still such an important gap of how do we actually bring that to real life? Because, you know, the example of what if you have one kid that's allergic and the one that's not, and you're trying to prevent in the one, but how do you not expose the patient who's allergic, the kid who's allergic, uh, and not have them having anaphylaxis while you're preventing it from the other one? And you know, again, a simple concept, but it makes it quite, quite, quite difficult. And so um, you know, I do think that there's still a lot of work to be done. And a lot of groups are doing this, you know, they're finding strategic ways that they can make this uh easier for families.

Rebecca Saff, MD, PhD, FAAAAI 21:50

So we know that there's this kind of window of opportunity for maybe like four to twelve months. Is four months better than six months, better than eight months early just better? Do we know anything? More specific about that window?

Edwin Kim, MD, FAAAAI 22:02

At least for peanut, it does look like some of the data as they kind of dug deeper into the leap data. Yeah, four months compared to 11 months seems to be the earlier does seem to be better. And again, how much of it is the immune system and sort of its uh malleability? How much of it is sort of again that oper that timing of like the longer you sort of are not introducing it, that you're opening the keeping the door open to become exposed and become allergic. And so it's probably a combination of both of those things. But this is an opportunity to kind of bring up like this seems to be sort of a window that we've identified for peanut and get it in there earlier four, five, six months. But if you keep in mind for the leap study itself, one of the inclusion criteria for kind of high risk was having egg allergy. And so that window for egg may not, four months may not be early enough. And sure enough, that's what we're seeing in some kids as they come to the clinic, they're, you know, again, one of their first foods is egg, and they're already allergic. And so, um, you know, how do you like what is the right window for the different foods? And then how do you introduce it in a kid that may not have like head control and be able to take solids? You know, some of these things. And so yeah, I, you know, again, it's a lot to be done.

Rebecca Saff, MD, PhD, FAAAAI 23:10

A lot to be done. Um, I'm sure you see many, you mentioned, you know, kind of this parent with a kid who has already a kid with food allergies now has a younger sibling. They're very nervous about introducing the food. We know that getting it in early is the most important thing to do. And it's really hard to get in to see an allergist, you know, so early. How do you try to kind of talk parents through the risk, how to introduce it? Um, what's kind of your advice?

Edwin Kim, MD, FAAAAI 23:34

Yeah, so I mean, there, I I really do try to emphasize sort of the timing is important. And so, I mean, waiting six months to come and see us is not a good thing, right? I mean, that's just number one, like uh we're gonna tell them the same thing, go ahead and introduce it. It is safe to do that. Uh, but again, that that window of time, that their their window may be closing sort of over that period of time. And so uh I think one of the biggest things I try to remind them of is going to be from everything we've seen from from LEAP, but also from these early OIT studies, these oral immunotherapy studies, it does seem like these younger kids, even when they do have reactions, thankfully, are much, much more likely to have the mild, uh, more easily manageable type of uh symptoms. And so, if anything, the biggest thing I've been trying to do is empower families, empower patients, really to get them to under, you know, um to kind of take control. Because I think that's one of the most frustrating parts of food out, is this sort of sense of lack of control, right? Everything around you is coming to get you. There's like uh, you know, airborne, this and that, and all these exposures that you can't see. And um, and it's really frightening. And so, really, much more the idea of you can do this. Uh, if you see these symptoms, use your common sense, use your parenting sense and treat it in this way. And, you know, really a lot of language around that. Um, and uh, but I I do think that that sense of control, uh, that ownership, that confidence, I think is super duper important. But really, if anything, just try to encourage them, just do it. Um, and you know, you got to work with each family because their level of anxiety, they're uh there, but also even that's sort of what's available at home, you know, is single parent, two parents, five kids, you know, all these factors matter. And so trying to make it sort of very specific to each family to talk through, okay, what are you dealing with? What is an opportunity, you know, what do you imagine could work? Let them come up with a plan. When do you think you could expose the peanut? Uh, what would that look like? But I think they're more likely to be able to follow through on it if they can share what they're thinking about, as opposed to me telling them what to do.

Rebecca Saff, MD, PhD, FAAAAI 25:26

And then immunotherapy for food, similarly, is do we think earlier is better? Um, is you know, where is the benefit start? You start to lose some of the benefit just because of age.

Edwin Kim, MD, FAAAAI 25:36

Yeah, so it does seem like that has also come true as well. So this window of opportunity to prevent seems to kind of uh also be a window of opportunity to treat as well. And so we've had several now studies uh of oral immunotherapy really focused on peanut, um, but basically demonstrating that can it work across ages? Sure. Um, but it does seem like the 18-year-old maybe doesn't respond quite as strongly as the 12-year-old, doesn't respond quite as well as the four, and then even down to the age one. And so the study that we talk probably the most about is the impact study. And so this was an oral immunotherapy focused on one to four-year-old toddlers, um, which I think is directly relevant to this conversation because we're not going to prevent all of allergy. Um, but one thing we are gonna see is that the ones that are allergic, we're gonna diagnose them earlier. And so, what can we do if we catch someone at say nine months and is allergic? And so, this impact study is great uh because it's focused on that group. Uh, and sure enough, what they found is uh these kids, again, they have reactions, but like I mentioned previously, that uh they seem to be definitely much more mild and moderate, much more manageable. Um, but after two and a half years of treatment, we actually had um uh a large proportion of patients actually eating full serving sizes. So not just uh, you know, a little bit of protection like we might see in the older cohorts, uh, but essentially eating full serving sizes of peanut without symptoms. Um and then a subset of those, even six months later, that protection was still there. And so we've used the term remission for it because that's probably you know, I think that the best way we can think about it is uh is relapse possible? Sure. But at least for the six-month period of time, this level of protection uh up to a degree of full serving size was still there. And that's something that I don't know that we've seen in older groups and uh can we see it in older groups? And so uh it does seem um like those toddler tolerate the treatment better, but also can get these high threshold uh benefits and then longer lasting benefits as well.

Rebecca Saff, MD, PhD, FAAAAI 27:28

And which do you foods do you think that's most important too? Because certainly things like egg and milk, we think about kids outgrowing them for the most part, but then some kids don't. Do we know that this will this work with foods outside of just peanut?

Edwin Kim, MD, FAAAAI 27:41

Yeah, so I mean, right now our thoughts are yeah, I mean, we it should work. And we've done studies for for milk allergy, we've done studies for for egg allergy, and then uh these days there's a lot of attention on tree nuts. Uh and cashew in particular seems to be really um, whether it's a change or if it's just that there's more cashew foods available or a combination of both, I do feel like everyone I talk to is saying they're seeing so much more cashew allergy in their clinics. And so uh I do get the sense that we're going to have similar types of uh efficacy um across all these foods and then a similar sort of benefit to getting in there early. Um, I do want to take a quick moment to kind of talk about milk or egg, though, because one of the things that kind of comes up is this idea of, oh, they're gonna outgrow it anyway, which uh yes, I totally agree with. But I think one thing that I talk to families about in clinic though is like even if if you have milk allergy at age one and you outgrow by age eight, um, that's still seven years of a food that's everywhere, right? I mean, it's like the milk exposure. So peanut exposure, you know, baked goods, maybe desserts and stuff like that. But in a lot of cases, like, you know, again, it's gonna be pretty well defined. But man, if you think about milk or egg, that is in everything. And so, you know, I don't think it's right for us to automatically say, oh, they're gonna outgrow it, and uh treatment would not be beneficial because I think that time that they have the allergy, I think the risk of exposures, uh the allergic reactions, and then the quality of life issues that come from trying to avoid this uh are tremendous. And so I think there will be some patients where they're like, you know, in the meantime, while I'm waiting to outgrow it, it absolutely makes sense to be treated. Others may be good to wait.

Rebecca Saff, MD, PhD, FAAAAI 29:18

And so where do you think the food allergy kind of research is heading in terms of, you know, we can't necessarily treat everyone with immunotherapy? Is there a microbiome effect that we can use to benefit? Is there um are there other methods that we can introduce at home versus having to come into the clinic every two weeks to updose immune, you know, biomarkers? What do you think is on the horizon?

Edwin Kim, MD, FAAAAI 29:40

Yeah, I mean, I think there's sort of two directions. Um, the first one I'll talk about is going to be more your global biologics. Um, and biologics are everywhere, especially in the field of allergy for sure. But I do bring that up first because the biggest benefit that the biologics can provide that I can see right now is that it's um they are just naturally allergen agnostic. And so we know that at least half of the patients, if not more, that we see are allergic to more than one food. And the allergen-specific approaches, as much as we've seen good data, including the starting young, you know, when you're talking about two foods, three, four, five, it gets harder and harder and harder. Um, and so I do think the biologics can bring that benefit of a single treatment, maybe able to um to manage your milk, egg, peanut, and your cashew allergies all simultaneously. And so for some families, that's going to be the ticket. That's what they need. Some of these biologics uh are also going to be able to take care of comorbid diseases as well. So if you have multiple food allergies, but you also happen to have, say, atopic dermatitis, or maybe you have um asthma, the thought of a single medicine potentially helping with all those uh is quite attractive, I think, um, for certain families as well. So there's gonna be a lot of work sort of in that area uh for sure. And so that's one area that we need to keep working on. At the same time, though, we know that those none of those biologics at the moment seem to be disease modifying, meaning like you're on the medicine, you get you have to stay on the medicine to maintain that benefit. And once you stop it, the allergy is still there and it's right back. And so I don't think we're done with the immunotherapies because really, again, our hope with immunotherapy is like what we've seen for venom allergy and what we've seen for aero allergens, we want to get to tolerance. We want to train your immune system to actually not be allergic anymore. And so, you know, I mentioned remission for the oral immunotherapy with peanut. It was a subset of those kids, about 20% of kids that got that. So, how do we get that more? How do we increase that? How do we um, you know, not have it restricted to the one or two year olds? How do we get a 12-year-old to remission and stuff? And so, really, I think what I'm imagining and what I'm excited about is going to be immunotherapy plus, whether it's OIT plus, sublingual plus, whatever. And what I mean by pluses, are there adjuvants, are there additives, are there things that we can provide at the same time that would kind of set up the immune system to be more likely to go towards tolerance and then expose the food in immunotherapy in that sort of setting? And so we'll see. I mean, I think there has been a lot of interest in this idea whether it's going to be, again, things that can set up the microbiome, uh, prebiotics, probiotics, anything along those lines, bacterial lysates, things that can work in that way. You know, maybe there are these sort of innate immune type of things, these uh TLR uh agonists, you know, toll-like agonists and stuff like that, you know, whatever it may be. But are there things like that that can help set up the immune system so that the same immunotherapy uh but can actually get us a stronger and a more lasting benefit?

Rebecca Saff, MD, PhD, FAAAAI 32:30

Yeah, definitely. So definitely have your kids go out, play in dirt, and have them eat all the foods early, everything we can do to have a healthy immune system.

Edwin Kim, MD, FAAAAI 32:39

Yep. Yep.

Rebecca Saff, MD, PhD, FAAAAI 32:40

Um, so are there take-home messages you'd like to make sure that people kind of have in mind as they go forward?

Edwin Kim, MD, FAAAAI 32:46

Yeah, I mean, I think one of the things that I mean this goes back to right from the beginning of thinking of sort of my training and sort of where things were and where things are now. I mean, there has been this paradigm shift, right? And you know, I mentioned about control, and I do think that all this ties together of this sort of defensive, like, hey, you have an allergy, sit back and wait for something bad to happen. Here's your epi pen, and then you know, um, if something bad happens, use it. And, you know, I mean, it's easy to see, like, oh my gosh, that's terrible, like to have to live in that way. And so now this shift of no, we're not gonna wait and let food allergy control us, but we're gonna actually do something about it, we're gonna be proactive towards it. And I think that's the biggest take-home message is that I think finally we can do that. And so up front, we can do things to try to prevent the allergy, get that food in there early. Um, you know, some of these play in the dirt, like you mentioned, a lot of these different things take care of the skin. There are things we can do up front to try to prevent it. If we happen to become allergic, okay, that's okay too. So again, it's not to sit back and wait for something bad to happen, but hey, there's these immunotherapies, um, there's biologics, there's things that are coming. And maybe our decision is going to be well, you know, none of those are for me now, but at least it's a decision now. Now we're talking about, okay, do we wait for the next best thing? Uh, do we avoid it because it's not such a big deal in our family, or do we do an immunotherapy or biologic? And so, you know, I think uh we've made a lot of progress. We have work to be done, but I'm really excited about where things are now.

Rebecca Saff, MD, PhD, FAAAAI 34:11

Yeah, having multiple options. I love that giving the control back to families rather than them just having to be defending against these allergens that are attacking their kids. So that's right. I love it. Well, thank you so much. I think this is fantastic, and I look forward to seeing the next phase of studies.

Edwin Kim, MD, FAAAAI 34:27

Yep. Thank you very much.

Rebecca Saff, MD, PhD, FAAAAI 34:30

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