Immunotherapy for food allergy: Promise and progress

Food allergy is a life-altering and potentially life-threatening condition affecting millions of children in the United States. Recent reports place the prevalence of food allergy in the pediatric population at about 8%, but also provide evidence that it is becoming increasingly more common.^1,2 Its seriousness is highlighted in part by data showing food allergy to be the most common cause of fatal and recurring anaphylaxis in children and adolescents.³ Living with constant fear of accidental ingestion and its potential sequelae, it is not surprising that patients with food allergy and their families experience a tremendous psychosocial and quality-of-life burden.⁴

The standard of care for food allergy involves nutritional counseling, allergen avoidance, and the ready availability of injectable epinephrine to treat acute reactions arising from accidental allergen exposure. Clearly, however, better options are needed, and allergen-specific immunotherapy (SIT) for food allergy is an area of active research.

With SIT, patients are exposed to escalating doses of the culprit allergen(s) in order to induce desensitization and, ideally, tolerance. Although SIT is considered as safe and effective for managing patients with allergic asthma, allergic rhinoconjunctivitis, and stinging insect allergies,⁵ its use for food allergy is still experimental.^6,7

Research with SIT for food allergy has been conducted investigating epicutaneous, sublingual, and oral routes of allergen administration. Of these approaches, oral immunotherapy (OIT) is generating particular excitement.

Multiple groups have published research on their experience with OIT for the most common food allergens, including cow’s milk, egg, peanut, and tree nuts. Using various protocols for allergen dose escalation, OIT investigators have reported achieving desensitization rates ranging from about 45% to 75%.⁸ In addition, studies exposing individuals to an oral food challenge at intervals of time after stopping OIT provide evidence that some individuals (25% to 40%) develop tolerance to the inciting antigen, at least in the short term.⁹

With dose escalation carried out in a controlled and supervised setting, OIT also has been reasonably safe.^6,9 However, safety remains a concern because treatment-related adverse events are common and have included severe reactions requiring epinephrine injection along with reports of the development of eosinophilic gastrointestinal disorders.^6,8

Therefore, experts agree there is much work yet to be done before OIT is ready to be used as a routine clinical treatment for patients with food allergies. Desensitization protocols need to be refined and then demonstrated safe and effective in multicenter, randomized, controlled clinical trials. In addition, more information is needed on the risk of resensitization, and there is interest in identifying biomarkers as potential predictors of desensitization responses and the development of tolerance.

Under the direction of Kari Nadeau, MD, PhD, the Stanford Alliance for Food Allergy Research (SAFAR) has been a leading center for investigating OIT for severe food allergies. The SAFAR team is focusing on both clinical studies and basic science research, and earlier in 2014 they published important findings in both of these areas.^10-12

In an interview with Contemporary Pediatrics, Nadeau, who is associate professor of pediatrics, Allergy and Clinical Immunology, Stanford School of Medicine, California, and, by courtesy, of otolaryngology, Head and Neck Surgery, at Lucille Packard Children’s Hospital at Stanford, discussed this research and other topics relating to food allergy treatment and prevention.

Q. What is the current status of immunotherapy for food allergy?

Dr. Nadeau: Immunotherapy has been used successfully for managing patients with allergies caused by environmental aeroallergens, such as grass or tree pollen and animal dander, and it is now being evaluated for food allergy.

Different types of immunotherapy are being investigated for food allergy-sublingual, epicutaneous, and oral-and, potentially, patients will have choices as to what their therapy will look like in the future. Importantly, all immunotherapy for food allergy is currently experimental. Currently, there is no food allergy therapy that is approved by the US Food and Drug Administration (FDA).

Based on encouraging results with OIT, we have hope about its promise for patients with food allergies. However, OIT does not work predictably in all patients, and according to findings from research conducted so far, the majority of patients do not achieve a fully sustained effect if they stop allergen exposure. In addition, there are safety issues that accompany all immunotherapy protocols. So, we need to move forward with our research in order to develop therapies that, in the end, are successful, offer good safety, and provide long-term tolerance. Various strategies that are being investigated now show promise for helping us achieve these goals. Combining other therapies with immunotherapy would be one of these approaches.

Q. Are you referring to concomitant use of anti-immunoglobulin E (IgE) therapy?

Dr. Nadeau: Treatment with the anti-IgE antibody omalizumab (Xolair) that prevents allergic cell activation is one adjunctive therapy, and we reported on its use in an open-label manner in rush OIT protocols for single and multiple allergens where it allowed us to rapidly escalate the dose in a safe manner.^11,13 We are excited that other sites will also be investigating this technique, and we will be conducting a Phase 2, randomized, placebo-controlled, blinded study in multiple centers to further determine its efficacy and safety for multifood OIT.

There are other investigational products in development, including an herbal formula using traditional Chinese medicine or introducing heat-treated foods that might have reduced allergenicity. For example, there is some evidence that persons with allergies to egg or milk can be desensitized through exposure to baked product, and there are protocols investigating that approach as an OIT method.

Q. Your center was the first center in the United States to conduct research looking at simultaneous desensitization to multiple food allergens. Are these studies being conducted elsewhere now?

Dr. Nadeau: To our knowledge, ours is the only food allergy center in the world to have undertaken a study of simultaneous OIT for multiple food allergens, but we hope we won’t keep that distinction for much longer. Thanks to the cooperation and guidance of the FDA, other sites will be starting such studies soon, and we are grateful to see this area of research expanding.

Q. Can you give any estimate as to how long it might be before OIT becomes approved as a treatment for food allergy?

Dr. Nadeau: That question requires a careful response. Obviously, the FDA needs to complete its comprehensive review. That is an important process for maintaining patient safety, which is always our top priority. It is possible that if all goes well, OIT for a single allergen, like peanut, might be approved in another 2 or 3 years, but it is always hard to make such predictions. Approval of OIT protocols involving adjunctive therapy, such as with omalizumab, will take longer.

However, I think the message should be that there has been a lot of progress in the past few years, and there is a lot of excitement, promise, and hope now as there are many sites actively studying immunotherapy for food allergy across the globe. In addition, I would say we would not be able to make any progress without people participating in clinical studies designed to test whether immunotherapy is safe and effective. Getting patients to enter into these important clinical trials is critical.

I would also note that there is much important research under way at Stanford to determine if we can use transformative non-OIT therapies to potentially find a long-term cure for patients with food allergy. I am excited about using these non-OIT methods to create a safe and effective and easy-to-use therapy.

We are also trying to elucidate the possible causes of food allergy in order to identify ways to prevent it. Likely there are environmental and/or nutritional factors that are potential risk factors for food allergy and that are in our control to change to improve outcomes.

Q. You have been doing some research looking at the immunologic changes that occur during the allergic reaction and with desensitization. Part of this is aimed at identifying predictors for tolerance. You recently published a paper on this subject.¹² Do you want to speak a little bit about this?

Dr. Nadeau: The average child or adult with peanut allergy that enters into a clinical study of OIT might eventually be able to eat a tablespoon of peanut butter with no allergic reaction, which is really exciting for that individual. However, although these patients are grateful to be desensitized, they may not want to have to continue eating peanuts in some form every day. With that in mind, we did a study to see if we could identify a marker of tolerance in desensitized patients 3 months after they had discontinued OIT and abstained from eating peanuts. In our group of 20 patients, 35% tolerated the oral challenge after being off therapy for 3 months.

We looked at a number of immune cell characteristics to see if we could find any feature that distinguished between the tolerant and nontolerant patients, and in this very small pilot study, we found an epigenetic marker in the antigen-induced regulatory T cells that was associated with the clinical outcome of tolerance the way that we defined it in the protocol.

We have to be careful when discussing these results. First, we are referring to the positive outcomes as sustained unresponsiveness rather than tolerance because we don’t know how long the benefit will last, but it is exciting that we found DNA changes corresponding to the unresponsiveness. Now we have to see if the results can be replicated in a larger Phase 2 study.

I would also point out that there are a lot of researchers, not just me, who are doing studies in this area, and that the pathophysiology of allergies is very complex with at least 32 different immune cells involved. Therefore, we probably need to think about a composite set of biomarkers when trying to predict the success of immunotherapy. I think we are getting there, and that is what I am excited about as a researcher in this field.

Q. Although OIT is not approved, some community allergists may be offering it. What are your messages for pediatricians in terms of finding out about Institutional Review Board (IRB)-approved clinical trials and referring patients to those?

Dr. Nadeau: We understand there are private allergists who might be doing OIT in the community because they also want to offer hope and promise to their patients, and on their behalf, I am sure they are trying to do it as carefully as possible, knowing the treatment is experimental and there are risks. In our academic setting, we recommend OIT be done under the supervision of well-trained hospital staff within the context of an IRB-approved clinical trial, and I would recommend that if a pediatrician was interested in referring a patient for OIT, he or she should go to www.clinicaltrials.gov to see if there is a clinical trial site available nearby or refer the patient to an allergy-immunology–trained specialist to get more information.

Q. You also mentioned earlier that there is research looking into possible strategies for minimizing the risk of developing food allergy. Currently, what should pediatricians be telling parents of newborns about introducing foods or strategies that might limit the risk of a child developing food allergy?

Dr. Nadeau: This was the topic for an article published last year in the Journal of Allergy and Clinical Immunology: In Practice.¹⁴ It is interesting that in the past, the American Academy of Pediatrics suggested that children not eat certain foods until aged 2 or 3 years, but this advice was not based on specific data. Now, upon careful review of the available evidence, including some recent research, it appears that introducing early diversification in foods, between 4 and 6 months of age, might be helpful rather than harmful. There is also support for eating a Mediterranean-style diet rich in vegetables and fruits rather than consuming a diet filled with high-fat foods.

Of course, children who develop eczema or signs and symptoms of allergy after eating a particular food should be evaluated by a physician. Diversifying the diet is thought to be a step toward decreasing the risk of food allergy in the general population, but it is not a guarantee for preventing food allergies in the individual.

Q. You also mentioned there is a genetic component to food allergies. What information might pediatricians give to parents that would be relevant to this issue?

Dr. Nadeau: In general, there is an increased risk of allergies in children of parents who have any type of allergy, and the child may have a completely new type of allergy. So, if there is a history of drug allergy, hay fever, asthma, or allergy to animal dander in the parent, the child might have food allergy. However, there are many children with food allergies whose parents have no allergies whatsoever. The development of food allergy seems to depend on epigenetic and genetic factors along with an environmental component, and there is a lot of research ongoing in this area to understand the risk and mechanisms.

Q. Do you have particular messages for readers about what they can do to help fuel continued advancements in food allergy research?

Dr. Nadeau: I hope that parents and pediatricians will find out more about the field and ask more questions. Of course, for any area of research that is up and coming, the more resources we can get, the more people we can train to do the needed research, and then the more answers we will be able to have for patients. Improving care for patients and their families is our utmost priority.

REFERENCES

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2. Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9-e17.

3. Huang F, Chawla K, Järvinen KM, Nowak-Wegrzyn A. Anaphylaxis in a New York City pediatric emergency department: triggers, treatments, and outcomes. J Allergy Clin Immunol. 2012;129(1):162-168.

4. Sicherer SH, Noone SA, Muñoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. 2001;87(6):461-464.

5. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 suppl):S1-S55. Erratum in: J Allergy Clin Immunol. 2011;127(3):840.

6. Syed A, Kohli A, Nadeau KC. Food allergy diagnosis and therapy: where are we now? Immunotherapy. 2013;5(9):931-944.

7. Kostadinova AI, Willemsen LE, Knippels LM, Garssen J. Immunotherapy-risk/benefit in food allergy. Pediatr Allergy Immunol. 2013;24(7):633-645.

8. Moran TP, Vickery BP, Burks AW. Oral and sublingual immunotherapy for food allergy: current progress and future directions. Curr Opin Immunol. 2013;25(6):781-787.

9. Jones SM, Burks AW, Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous. J Allergy Clin Immunol. 2014:133(2):318-323

10. Bégin P, Winterroth LC, Dominguez T, et al. Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy Asthma Clin Immunol. 2014;10(1):1.

11. Bégin P, Dominguez T, Wilson SP, et al. Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using omalizumab. Allergy Asthma Clin Immunol. 2014;10(1):7.

12. Syed A, Garcia MA, Lyu SC, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol. 2014;133(2):500-510.

13. Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol. 2011;127(6):1622-1624.

14. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013;1(1):29-36.

Ms Krader has 30 years of experience as a medical writer. She has worked as both a hospital pharmacist and a clinical researcher/writer for the pharmaceutical industry and is presently a freelance writer in Deerfield, Illinois. She has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.