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Varying Efficacy and Safety Among Food Allergy Immunotherapy Methods
By Karishma Sira, Biological Sciences ‘21
Author’s Note: This review was originally written for my UWP104F class in Winter Quarter 2021. While environmental allergies are well known to the public, many people are unaware of the social, mental, financial, and most importantly, physical costs of food allergies. I highly benefited from getting treated for food allergies through immunotherapy, so I want to make these methods more known. I want to raise awareness on the available non-avoidant treatments catered to food allergy sufferers and inform readers that these methods are important developments happening in the world of food allergy immunotherapy. This article will also explain the basic mechanisms of immunotherapy, the differences between each delivery method, the relative effectiveness of these methods, and the risks and benefits of each method. These factors should all be considered when recommending a specific method to an allergic individual.
Food allergies are becoming an increasingly common global health crisis. The various consequences of living with food allergies reduces the quality of life for those affected [1]. Aside from the immediate dangers of severe allergic reactions, there is a significant amount of social restrictions and anxiety involved. Dealing with food allergies costs American individuals and families 25 billion dollars annually [2]. Avoidance diets are the most common way to treat food allergies, but they are statistically unsustainable: 75% of peanut-allergic children get accidentally exposed to peanuts by the time they are 5 years old [1]. As a result, allergy immunotherapy is an important developing preventative treatment that can allow individuals to consume allergens to improve quality of life.
There are three main emerging treatments: oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT). All three use different delivery methods to introduce the patient to allergens to achieve desensitization. The different delivery methods may contribute to the different levels of success observed between them.
The guiding principle of food allergy immunotherapy, regardless of delivery method, is to induce a state of prolonged desensitization–defined as an increase in tolerance threshold–to an allergen [3]. This may be achieved by maintaining consumption of allergen over time through doses tailored to the patient’s observed tolerance threshold. Tolerance thresholds are determined with food challenges, where the patient consumes allergens until they experience notable allergic symptoms [4]. Desensitization may be gradually achieved through increases in dosage [3, 4]. Allergen doses slowly increase over time as the patient’s tolerance increases. Administering the allergen this way is thought to familiarize the body with it so that the immune response to the allergen gradually becomes less severe over time [5].
Generally, the immune response to allergens is mediated by allergy-specific antibodies called Immunoglobulin E (IgE). Once a food allergen has been ingested and detected by the immune system, IgE activates immune cells that cause inflammation and other allergy symptoms. Immunotherapy attempts to change the immune response so that allergens stimulate non-allergy specific antibodies like Immunoglobulin G (IgG) [5]. IgG antibodies produce a normal immune response to foreign bodies like infections and viruses. Training the body to respond with IgG prevents the allergic response, eliminating adverse allergic symptoms.
Immunotherapy aims to create a state of long term desensitization known as sustained unresponsiveness (SU). By achieving SU, patients are more likely to retain tolerance even after they stop taking the regular, repeated doses of allergen. Patients with SU can often freely be in the presence of their allergens or even consume them [3, 4]. SU is not considered a “cure” of allergies. Immunotherapy simply aims to change the Immunoglobulin E-mediated allergic response to a less drastic response that has little to no effect on quality of life [1]. SU is less commonly achieved than desensitization across all delivery methods, with only a small subset of patients reaching SU after years of therapy [6]. Nonetheless, SU remains the ideal end goal for all patients [3].
Delivery Methods
Across all studies cited in this literature review, delivery methods vary in efficacy depending on the food allergen being treated. Discussing the efficacy of each method for individual food allergens would thus require extensive examination and comparison of many individual studies. This level of specificity is not necessary to explain or compare the efficacies of the three immunotherapies. The duration and safety of each treatment seems to widely vary based on the particular allergic response, tolerance threshold, and specific allergens of an individual. Despite these differences, however, much of the research yields consistent results in the overall relative efficacy of each method. As such, this review will describe a general consensus about the effectiveness of each delivery method across many studies.
Delivery Method #1 – Oral Immunotherapy
The first food allergy immunotherapy delivery method, which has recently received Food and Drug Administration (FDA) approval for peanut allergen [7] is oral immunotherapy (OIT). In OIT, the patient ingests allergen protein often in powder form and mixed with other non-allergenic food [5].
OIT has yielded the most promising clinical results out of all immunotherapy delivery methods [5]. Most patients treated with OIT have reached desensitization, though SU is less commonly observed [3]. Adverse allergic reactions are reasonably likely to occur during OIT, though most reactions are mild. All reactions can be promptly addressed within a clinical or hospital setting. Despite this, individuals with severe and fast-acting allergic reactions (e.g. anaphylaxis) may still face risks to their physical well-being [3, 6]. As of now, only an OIT treatment, known as PalforziaⓇ, for peanut allergen has been approved by the FDA out of all potential immunotherapies. At this point in time, it has passed clinical trials and requires additional risk assessments, education, and patient counseling for use [7].
Adjuvant medications–used in combination with a treatment to enhance or modify its effects are being examined as additional safety measures to make OIT safer. Omalizumab is a monoclonal antibody, an antibody cloned from existing antibodies that can be taken as medicine to assist immune functions. Omalizumab selectively binds to IgE, which occupies IgE enough to suppress the allergic response [8]. Omalizumab appears to have no bearing on the effectiveness of the desensitization process [3]. However, it has been shown to speed up the process and decrease incidence of adverse allergic reactions. For common allergens like milk and peanut, little to no adverse reactions were observed when Omalizumab was administered to subjects [8]. However, further research and clinical trials with larger sample sizes and a wider array of allergens must be conducted before Omalizumab can be universally used as a safety protocol for food allergy immunotherapy [8].
Delivery Method #2 – Sublingual Immunotherapy
The second delivery method is sublingual immunotherapy (SLIT). SLIT requires that liquid or dissolvable extracts of allergens be regularly administered under the tongue, held there for a time, and then swallowed [5]. Using this method, the allergen can be mainly taken into the body by way of antigen presenting cells in the sublingual mucosa found under the tongue. This route avoids enzymes encountered during gastric digestion that might change the structure of the allergen protein. This is useful in ensuring that the immune system becomes fully desensitized to the correct allergen [6].
One advantage of SLIT is its safety; adverse allergic reactions and anaphylaxis are not commonly observed [5, 6]. Additionally, using SLIT before OIT is highlighted as a potential benefit. Patients who experience adverse reactions with OIT generally are advised to use SLIT as a stepping stone treatment. This lets them build enough desensitization to make OIT a more viable option, as they experience less side effects [5].
Delivery Method #3 – Epicutaneous Immunotherapy
The third delivery method in food allergy immunotherapy is epicutaneous immunotherapy (EPIT). Immune cells in the skin called Langerhans cells help introduce the allergen to the body when dermal patches are applied to the skin [5, 9]. Patches are kept on for increasingly longer durations and replaced as instructed by a physician until the patient is mostly unresponsive to the allergen. At this point, patches must still be worn to maintain results, but need only be replaced every 24 hours [2].
Using this route to absorb allergens successfully prevents entry to vasculature, which is thought to limit severe systemic allergic reactions and only results in mild, cutaneous reactions [1, 9]. Similar to SLIT, this makes EPIT’s safety profile better than OIT’s. Additionally, EPIT does not place restrictions on the patient’s lifestyle and does not require close clinical observation like OIT or SLIT [2].
Comparing Delivery Methods
As mentioned earlier, OIT is largely considered the most effective of the three immunotherapies described. Most patients are successfully desensitized and SU, though still infrequent, it occurs more often than other methods [3, 5].
SLIT has shown modest levels of desensitization, but is overall considered less effective than OIT, showing less immunologic changes over time [6]. It does not appear to confer high levels of SU [5]. It is unknown whether this is attributed to the fact that most patients appear to struggle with completing the recommended duration of treatment [9].
EPIT also demonstrates levels of desensitization comparable to SLIT, with 28-50% of patients showing tolerance to their allergen on average [1, 2]. SU has not been well documented in either EPIT or SLIT [1], which seems to be the main reason why they do not have FDA approval [2].
Conclusions
Preventative food allergy immunotherapy has been a developing area of study due to a global increase in food allergy incidence [5]. Three prominent immunotherapy delivery methods have emerged with differing efficacies and safety profiles.
OIT is widely considered the most clinically efficient and promising delivery method, since it consistently produces desensitization [5]. SLIT shows less consistent desensitization [6] and maintaining treatment is difficult for patients. EPIT shows similar results to SLIT [9]. While SU is not commonly achieved, it is more common in OIT [1, 3], which may explain why the only FDA-approved food allergy immunotherapy is OIT for peanut allergen [7].
The safety and convenience of each method may also affect patient choice. OIT may be the most effective and quick-acting, but it also runs the largest risk of adverse reactions, which warrants close clinical attention during treatment [3, 6]. In contrast, SLIT does not seem to cause many adverse reactions and is encouraged as a stepping stone treatment for patients that would like to move on to OIT once more tolerance to their allergen is built up. This practice seems to make OIT much safer [5] along with the use of medications like Omalizulab [8]. EPIT is also safer than OIT but has the added advantage of being a convenient and low maintenance treatment [5, 9]. At maintenance, dermal patches used for EPIT only need to be replaced every 24 hours, no clinical observation is required, and there are no restrictions placed on the patient’s lifestyle [2].
As allergies become more common across the globe, more children struggle to adhere to avoidance diets and become vulnerable to accidental exposure to allergens [1]. Immunotherapy methods have developed in the hopes of increasing the quality of life of these food allergic individuals [1]. Future research may be able to improve on the observed effects and safety of immunotherapy. Ultimately, any progress will be able to help food allergy sufferers improve their quality of life.
References:
- Costa, C., Coimbra, A., Vítor, A., Aguiar, R., Ferreira, A. L., & Todo-Bom, A. (2020). Food allergy – From food avoidance to active treatment. Scandinavian journal of immunology, 91(1), e12824. doi:10.1111/sji.12824
- Kim, E. H., & Burks, A. W. (2020). Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy. Allergy, 75(6), 1337–1346. doi:10.1111/all.14220
- Wood R. A. (2017). Oral Immunotherapy for Food Allergy. Journal of investigational allergology & clinical immunology, 27(3), 151–159. doi:10.18
- Marcucci, F., Isidori, C., Argentiero, A., Neglia, C., & Esposito, S. (2020). Therapeutic perspectives in food allergy. Journal of translational medicine, 18(1), 302. doi:10.1186/s12967-020-02466-x
- Burks, A. W., Sampson, H. A., Plaut, M., Lack, G., & Akdis, C. A. (2018). Treatment for food allergy. The Journal of allergy and clinical immunology, 141(1), 1–9. doi:10.1016/j.jaci.2017.11.004
- Scurlock A. M. (2018). Oral and Sublingual Immunotherapy for Treatment of IgE-Mediated Food Allergy. Clinical reviews in allergy & immunology, 55(2), 139–152. doi:10.1007/s12016-018-8677-0
- Caccomo, S. (2021). FDA approves first drug for treatment of peanut allergy for children. U.S. Food and Drug Administration. <https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children>.
- Dantzer, J. A., & Wood, R. A. (2018). The use of omalizumab in allergen immunotherapy. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 48(3), 232–240. doi:10.1111/cea.13084
- Reisacher, W. R., & Davison, W. (2017). Immunotherapy for food allergy. Current opinion in otolaryngology & head and neck surgery, 25(3), 235–241. doi:10.1097/MOO.0000000000000353
The Scientific Cost of Progression: CAR-T Cell Therapy
By Picasso Vasquez, Genetics and Genomics ‘20
Author’s Note: One of the main goals for my upper division UWP class was to write about a recent scientific discovery. I decided to write about CAR-T cell therapy because this summer I interned at a pharmaceutical company and worked on a project that involved using machine learning to optimize the CAR-T manufacturing process. I think readers would benefit from this article because it talks about a recent development in cancer therapy.
“There’s no precedent for this in cancer medicine.” Dr. Carl June is the director of the Center for Cellular Immunotherapies and the director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. June and his colleagues were the first to use CAR-T, which has since revolutionized personal cancer immunotherapy [1]. “They were like modern-day Lazarus cases,” said Dr. June, referencing the resurrection of Saint Lazarus in the Gospel of John and how it parallels the first two patients to receive CAR-T. CAR-T, or chimeric antigen receptor T-cell, is a novel cancer immunotherapy that uses a person’s own immune system to fight off cancerous cells existing within their body [1].
Last summer, I had the opportunity to venture across the country from Davis, California, to Springhouse, Pennsylvania, where I worked for 12 weeks as a computational biologist. One of the projects I worked on was using machine learning models to improve upon the manufacturing process of CAR-T, with the goal of reducing the cost of the therapy. The manufacturing process begins when T-cells are collected from the hospitalized patient through a process called leukapheresis. In this process, the T-cells are frozen and shipped to the manufacturing facility, such as the one I worked at this summer, where they are then grown up in large bioreactors. On day three, the T-cells are genetically engineered to be selective towards the patient’s cancer by the addition of the chimeric antigen receptor; this process turns the T-cells into CAR-T cells [2]. For the next seven days, the bioengineered T-cells continue to grow and multiply in the bioreactor. On day 10, the T-cells are frozen and shipped back to the hospital where they are injected back into the patient. Over the 10 days prior to receiving the CAR-T cells, the patient is given chemotherapy to prepare their body for inoculation of the immunotherapy [2]. This whole process is very expensive and as Dr. June put it in his TedMed talk, “it can cost up to 150,000 dollars to make the CAR-T cells for each patient.” But the cost does not stop there; when you include the cost of treating other complications, the cost “can reach one million dollars per patient” [1].
The biggest problem with fighting cancer is that cancer cells are the result of normal cells in your body gone wrong. Because cancer cells look so similar to the normal cells, the human body’s natural immune system, which consists of B and T-cells, is unable to discern the difference between them and will be unable to fight off the cancer. The concept underlying CAR-T is to isolate a patient’s T-cells and genetically engineer them to express a protein, called a receptor, that can directly recognize and target the cancer cells [2]. The inclusion of the genetically modified receptor allows the newly created CAR-T cells to bind cancer cells by finding the conjugate antigen to the newly added receptor. Once the bond between receptor and antigen has been formed, the CAR-T cells become cytotoxic and release small molecules that signal the cancer cell to begin apoptosis [3]. Although there has always been drugs that help your body’s T-cells fight cancer, CAR-T breaks the mold by showing great efficacy and selectivity. Dr. June stated “27 out of 30 patients, the first 30 we treated, or 90 percent, had a complete remission after CAR-T cells.” He then goes on to say, “companies often declare success in a cancer trial if 15 percent of the patients had a complete response rate” [1].
As amazing as the results of CAR-T have been, this wonderful success did not happen overnight. According to Dr. June, “CAR T-cell therapies came to us after a 30-year journey, along with a road full of setbacks and surprises.” One of these setbacks is the side effects that result from the delivery of CAR-T cells. When T-cells find their corresponding antigen, in this case the receptor on the cancer cells, they begin to multiply and proliferate at very high levels. For patients who have received the therapy, this is a good sign because the increase in T-cells indicates that the therapy is working. When T-cells rapidly proliferate, they produce molecules called cytokines. Cytokines are small signaling proteins that guide other cells around them on what to do. During CAR-T, the T cells rapidly produce a cytokine called IL-6, or interleukin-6, which induces inflammation, fever, and even organ failure when produced in high amounts [3].
According to Dr. June, the first patient to receive CAR-T had “weeks to live and … already paid for his funeral.” When he was infused with CAR-T, the patient had a high fever and fell comatose for 28 days [1]. When he awoke from his coma, he was examined by doctors and they found that his leukemia had been completely eliminated from his body, meaning that CAR-T had worked. Dr. June reported that “the CAR-T cells had attacked the leukemia … and had dissolved between 2.9 and 7.7 pounds of tumor” [1].
Although the first patients had outstanding success, the doctors still did not know what caused the fevers and organ failures. It was not until the first child to receive CAR-T went through the treatment did they discover the cause of the adverse reaction. Emily Whitehead, at six years old, was the first child to be enrolled in the CAR-T clinical trial [1]. Emily was diagnosed with acute lymphoblastic leukemia (ALL), an advanced, incurable form of leukemia. After she received the infusion of CAR-T, she experienced the same symptoms of the prior patient. “By day three, she was comatose and on life support for kidney failure, lung failure, and coma. Her fever was as high as 106 degrees Fahrenheit for three days. And we didn’t know what was causing those fevers” [1]. While running tests on Emily, the doctors found that there was an upregulation of IL-6 in her blood. Dr. June suggested that they administer Tocilizumab to combat increased IL-6 levels. After contacting Emily’s parents and the review board, Emily was given Tocilizumab and “Within hours after treatment with Tocilizumab, Emily began to improve very rapidly. Twenty-three days after her treatment, she was declared cancer-free. And today, she’s 12 years old and still in remission” [1]. Currently, two versions of CAR-T have been approved by the FDA, Yescarta and Kymriah, which treat diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) respectively [1].
The whole process is very stressful and time sensitive. This long manufacturing task results in the million-dollar price tag on CAR-T and is why only patients in the worst medical states can receive CAR-T [1]. However, as Dr. June states, “the cost of failure is even worse.” Despite the financial cost and difficult manufacturing process, CAR-T has elevated cancer therapy to a new level and set a new standard of care. However, there is still much work to be done. The current CAR-T drugs have only been shown to be effective against liquid based cancers such as lymphomas and non-effective against solid tumor cancers [4]. Regardless, research into improving the process of CAR-T continues to be done both at the academic level and the industrial level.
References:
- June, Carl. “A ‘living drug’ that could change the way we treat cancer.” TEDMED, Nov. 2018, ted.com/talks/carl_june_a_living_drug_that_could_change_the_way_we_treat_cancer.
- Tyagarajan S, Spencer T, Smith J. 2019. Optimizing CAR-T Cell Manufacturing Processes during Pivotal Clinical Trials. Mol Ther. 16: 136-144.
- Maude SL, Laetch TW, Buechner J, et al. 2018. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 378: 439-448.
- O’Rourke DM, Nasrallah MP, Desai A, et al. 2017. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 9: 399.