Category: Allergies

Existing Allergy Medication Unleashes Antitumour Immunity against Lung Cancer

Photo by Anna Shvets

Researchers from Mount Sinai report in Nature that they have identified an allergy pathway that, when blocked, unleashes antitumour immunity in mouse models of non-small cell lung cancer (NSCLC).

And in an early parallel study in humans, combining immunotherapy with dupilumab an Interleukin-4 (IL-4) receptor-blocking antibody widely used for treating allergies and asthma – boosted patients’ immune systems, with one out of the six experiencing significant tumour reduction.

“Immunotherapy using checkpoint blockade has revolutionised treatment for non-small cell lung cancer, the most common form of lung cancer, but currently only about a third of patients respond to it alone, and in most patients, the benefit is temporary,” says senior study author Miriam Merad, MD, PhD, at the Icahn School of Medicine at Mount Sinai.

“A big focus of our program TARGET is to use single cell technology and artificial intelligence to identify molecular immune programs that can dampen tumour immune response to checkpoint blockade.”

Also known as a PD1 inhibitor, checkpoint blockade is a type of cancer immunotherapy that can unleash the cancer-killing activity of T cells.

“Using single cell technologies, we discovered that the immune cells infiltrating lung cancers, as well as other cancers we studied, exhibited characteristics of a ‘type 2’ immune response, which is commonly associated with allergic conditions like eczema and asthma,” says first study author Nelson LaMarche, PhD, a postdoctoral research fellow in the lab of Dr Merad.

“These results led us to explore whether we could repurpose a medication typically used for allergic conditions to ‘rescue’ or enhance tutor response to checkpoint blockade,” says Thomas Marron, MD, PhD, co-senior author of the study.

“Strikingly, we found that IL-4 blockade enhanced lung cancer response to checkpoint blockade in mice and in six lung cancer patients with treatment-resistant disease. In fact, one patient whose lung cancer was growing despite checkpoint blockade had nearly all their cancer disappear after receiving just three doses of the allergy medication, and his cancer remains controlled today, over 17 months later.”

The researchers are encouraged by the initial results but emphasise the need for larger clinical trials to validate the drug’s efficacy in treating NSCLC.

Beyond the clinical trial findings reported in the current Nature paper, the investigators have now expanded the clinical trial, adding dupilumab to checkpoint blockade for a larger group of lung cancer patients, and are starting to investigate its use in early-stage lung cancer as well. Through these trials, they are searching for biomarkers to identify those cancer patients who might benefit from dupilumab treatment.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Predicting and Preventing Anaphylaxis During Food Allergy Tests

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A team of University of Michigan researchers developed a method that measures water loss from the skin to predict anaphylaxis during oral food challenges before it becomes clinically evident. The results are published in The Journal of Clinical Investigation.

Oral food challenges – when a patient ingests increasing doses up to a full serving of the suspected food allergen under supervision of a medical provider – are the diagnostic standard as skin and blood allergy tests have high false positive rates.

Although a highly accurate diagnostic test, patients often experience anaphylaxis during oral food challenges necessitating an epinephrine injection.

“This method could enhance the ability to detect and predict anaphylaxis during oral food challenges prior to the need for epinephrine, greatly improving patient safety and comfort,” said Charles Schuler, M.D., lead author of the study and an immunologist at Michigan Medicine.

Building on existing research

During anaphylaxis, the dilation or widening of the blood vessels increases heat and water loss from the surface of the skin.

Previous research has assessed facial thermography, which uses a specialized camera to detect heat patterns emitted from the skin, as a method to predict anaphylaxis.

However, this method requires optics expertise, tightly controlled conditions and for the patient to sit still for an extended period – making this an impractical choice, especially for assessing food allergies in children.

The researchers validated the use of transepidermal water loss, a measurement that represents the amount of water that escapes from a given skin area per hour, by comparing its ability to detect anaphylaxis with biochemical and clinical observation methods.

They found that transepidermal water loss increases during food allergy reactions and anaphylaxis.

The rise in skin water loss correlated with biochemical markers of anaphylaxis and substantially preceded clinical detection of anaphylaxis.

“Transepidermal water loss measurement can be done in office without specialized equipment, affixed to the skin and works in children making it a vast improvement from previous attempts at early anaphylaxis detection methods,” said Schuler.

Schuler’s research group is currently recruiting participants aged six months to five years old for a pilot clinical trial, Predicting Peanut Anaphylaxis and Reducing Epinephrine, that monitors transepidermal water loss from the forearm during a peanut allergy food challenge.

Results will help pinpoint values associated with anaphylaxis to determine “stopping rules” to end oral food challenges, hopefully reducing the need for epinephrine injections.

Source: Michigan Medicine – University of Michigan

Pre-existing Allergies Increase Risk of Experiencing Long COVID Symptoms

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In an analysis of published prospective studies of people of all ages with confirmed SARS-CoV-2 infection who were followed for at least 12 months, pre-existing allergic conditions were linked to higher risks of experiencing long-term symptoms associated with COVID, or ‘Long COVID’.  

The analysis, which is published in Clinical & Experimental Allergy, identified 13 relevant studies (with a total of 9 967 participants) published between January 1, 2020 and January 19, 2023.

Although the data as a whole from the studies suggested that individuals with asthma or rhinitis might be at increased risk of long COVID after SARS-CoV-2 infection, the evidence for these associations was very uncertain. Therefore, more robust epidemiological research is needed to clarify the role of allergy in the development of Long COVID.

“We need a better, harmonised definition of what is considered Long COVID for epidemiological studies of this sort. Regardless we will be updating our analysis once further studies have been published in the next few months,” said corresponding author Christian Apfelbacher, PhD, of the Institute of Social Medicine and Health Systems Research, in Germany.

Source: Wiley

Sublingual Immunotherapy for Peanut-Allergic Toddlers is Safer and More Effective

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A three-year clinical trial has shown that the sublingual immunotherapy (SLIT) is safe in peanut-allergic children ages one to four, with a greater likelihood of desensitisation and remission the earlier the treatment began. SLIT approach where the treatment is given as a small amount of liquid under the tongue, instead of peanut flour that is mixed with other food and then eaten like it is during oral immunotherapy, or OIT.

Published in the Journal of Allergy and Clinical Immunology, this is the first randomised, controlled trial to investigate – in this young age group – the efficacy and feasibility of SLIT.

The study included 50 peanut-allergic children between the ages of one and four, randomised to receive 4mg peanut SLIT versus placebo. Participants were randomised 1:1 to receive either peanut SLIT or placebo. Desensitization to peanut was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after three years of treatment.

Findings showed that peanut SLIT can be highly effective in treating peanut-allergic toddlers with almost 80% tolerating 15 peanuts without allergic symptoms after completing the treatment. With most typical peanut-allergic reactions being caused by one peanut or less, these results would translate into strong protection against exposures to peanut. In addition, researchers showed that remission of the peanut allergy may be possible after peanut SLIT with 63% of the toddlers maintaining their protection three months after stopping the treatment. These new findings show that early intervention with peanut SLIT is promising and warrants further development.

Led by Edwin Kim, MD, associate professor of paediatrics at the UNC School of Medicine, said: “From our prior studies in older children, we were optimistic that peanut SLIT could have a similar treatment effect in toddlers.

“However, what we found was even better. The desensitisation levels we saw were higher than expected and on par with levels we normally would only expect with oral immunotherapy. Just as important, rather than wearing off quickly, we were excited to see that over 60% stayed protected three months after stopping the treatment.”

One of the presumed strengths of the SLIT approach when compared to OIT has been its overall safety and simple administration. While most treatment side effects with OIT are mild to moderate, severe reactions requiring emergency treatment do occur and there remains a critical need to develop treatments with more manageable side effects.

“Peanut OIT is currently available and being offered by increasing numbers of allergists, however we are quickly learning that in addition to its known risk of allergic reactions, the actual doing of OIT can be very difficult for many families,” said Kim. “Peanut SLIT could be a good option to consider as it may be able to provide comparable levels of protection while being safe and easier to administer.”

Compared to OIT, the SLIT approach is likely to be a safer option, Kim said, with the most common side effect consisting of oral itching. Treatments that can protect children from allergic reactions while still being safe and practical for busy families can be life-changing, and researchers are hopeful that peanut SLIT can be one of those options.

“Even with the push to introduce peanut in early childhood in order to prevent the allergy, peanut allergy remains one of the most common food allergies,” said Kim. “A result of early peanut introduction is that we are diagnosing peanut allergy at younger and younger ages making it vitally important to develop treatments that can be safe and effective at preventing allergic reactions in these young children.”

Source: UNC School of Medicine

Does the ‘Hygiene Hypothesis’ Still Hold Water?

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Over the last few decades, there has been growing popularity for the ‘hygiene hypothesis’, which suggests that some level of microbial exposure helps protects against developing allergy. Now, an article published in Science Immunology by researchers from Karolinska Institutet challenges this hypothesis by showing that mice with high infectious exposures from birth have the same, if not an even greater ability to develop allergic immune responses than ‘clean’ laboratory mice.

Studies have suggested that certain infections might reduce the production of inflammatory antibodies to allergens and alter the behaviour of T cells involved in allergies. It has also been suggested that ‘good’ intestinal bacteria could shut off inflammation elsewhere in the body.

Robust allergic responses

Researchers have now compared the allergic immune response in ‘dirty’ wildling mice to those of typical clean laboratory mice. They found very little evidence that the antibody response was altered or that the function of T cells changed in a meaningful way. Nor did anti-inflammatory responses evoked by good gut bacteria appear to be capable of switching off the allergic immune response. On the contrary, wildling mice developed robust signs of pathological inflammation and allergic responses when exposed to allergens.

“This was a little unexpected but suggests that it’s not as simple as saying, ‘dirty lifestyles will stop allergies while clean lifestyles may set them off’. There are probably very specific contexts where this is true, but it is perhaps not a general rule,” says Jonathan Coquet, co-author of the study and Associate Professor at Karolinska Institutet.

More like the human immune system

The wildling mice are genetically identical to clean laboratory mice but are housed under ‘semi-natural’ conditions and have rich microbial exposures from birth.

“The immune systems of wildling mice better represent the human immune system and so we hope that they can bring us closer to the truth of how microbes act upon the body,” says Jonathan Coquet.

The findings contribute to the general understanding of how allergies may arise and may also have clinical implications. Using experimental infections to treat patients suffering from inflammatory diseases has also been attempted in recent clinical trials. For example, infecting people with worms or performing faecal transplantations has been proposed as a tool to combat inflammatory diseases. Newborns delivered through C-section, have had maternal faecal transplantation and bacterial supplementation with the aim of promoting good bacteria in the baby’s gut and the child’s future health.

Beneficial effects of exposure not clear as we’d like

“This field of research can provide important insights into how infections and microbes can be used to facilitate health, but it is still in its infancy. Our study is a reminder that general and broad exposures to microbes may not have the clear beneficial effects that we wish them to have,” says Susanne Nylén, co-author of the study and Associate Professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.


Can We Predict the Severity of Food Allergies Using Genetics?

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Researchers have discovered that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. The researchers reported their findings in the Journal of Allergy and Clinical Immunology.

The researchers, led by Ann & Robert H. Lurie Children’s Hospital of Chicago, found that the presence of an enzyme isoform called α-tryptase, which is encoded by the TPSAB1 gene, correlates with increased prevalence of anaphylaxis or severe reaction to food as compared to subjects without any α-tryptase.

“Determining whether or not a patient with food allergies has α-tryptase can easily be done in clinical practice using a commercially available test to perform genetic sequencing from cheek swabs,” said lead author Abigail Lang, MD, MSc, attending physician and researcher at Lurie Children’s and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If the biomarker is detected, this may help us understand that the child is at a higher risk for a severe reaction or anaphylaxis from their food allergy and should use their epinephrine auto-injector if exposed to the allergen. Our findings also open the door to developing an entirely new treatment strategy for food allergies that would target or block α-tryptase. This is an exciting first step and more research is needed.”

Tryptase is found mainly in mast cells, which become activated during allergic reactions. Increased TPSAB1 copy number which leads to increased α-tryptase is already known to be associated with severe reactions in adults with Hymenoptera venom allergy (or anaphylaxis following a bee sting).

Dr Lang’s study included 119 participants who underwent TPSAB1 genotyping, 82 from an observational food allergy cohort at the National Institute of Allergy and Infectious Diseases (NIAID) and 37 from a cohort of children who reacted to peanut oral food challenge at Lurie Children’s.

“We need to validate our preliminary findings in a much larger study, but these initial results are promising,” says Dr Lang. “We also still need a better understanding of why and how α-tryptase makes food allergy reactions more severe in order to pursue this avenue for potential treatment.”

Source: Ann & Robert H. Lurie Children’s Hospital of Chicago

Common Gut Microbiota Link to the Development of Childhood Allergies

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Several major childhood allergies may all stem from the gut microbiome gut, according to a new study published in Nature Communications. The research identifies gut microbiome features and early life influences that are associated with children developing any of four common allergies. The study, led by researchers at the University of British Columbia and BC Children’s Hospital, could lead to methods of predicting whether a child will develop allergies, and methods to prevent their development.

“We’re seeing more and more children and families seeking help at the emergency department due to allergies,” said Dr Stuart Turvey, paediatrics professor at UBC and co-senior author on the study, noting that as many as one in three children in Canada have allergies.

The study is one of the first to examine four distinct school-aged paediatric allergies at once: atopic dermatitis, asthma, food allergy and allergic rhinitis. While these allergic diseases each have unique symptoms, the Turvey lab was curious whether they might have a common origin linked to the infant gut microbiota composition.

“These are technically different diagnoses, each with their own list of symptoms, so most researchers tend to study them individually,” says Dr Charisse Petersen, co-senior author on the paper and postdoctoral fellow in the Turvey lab. “But when you look at what is going wrong at a cellular level, they actually have a lot in common.”

For the study, researchers examined clinical assessments from 1115 children who were tracked from birth to age five. Roughly half of the children (523) had no evidence of allergies at any time, while more than half (592) were diagnosed with one or more allergic disorders by an expert physician. The researchers evaluated the children’s microbiomes from stool samples collected at clinical visits at three months and one year of age.

The stool samples revealed a bacterial signature that was associated with the children developing any of the four allergies by five years of age. The bacterial signature is a hallmark of dysbiosis, or an imbalanced gut microbiota, that likely resulted in a compromised intestinal lining and an elevated inflammatory response within the gut.

“Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action,” says Courtney Hoskinson, a PhD candidate at UBC and first author on the paper. “We found a common breakdown in these mechanisms in babies prior to the development of allergies.”

Many factors can shape the infant gut microbiota, including diet, place and delivery method of birth and antibiotics exposure. The researchers examined how these types of influences affected the balance of gut microbiota and the development of allergies.

“There are a lot of potential insights from this robust analysis,” says Dr Turvey. “From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied.”

Now the researchers hope to leverage the findings to inform treatments that correct an imbalanced gut microbiota and could potentially prevent allergies from developing.

“Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime,” says Dr Turvey.

Source: University of British Columbia

Food Allergy in Infancy Linked to Childhood Asthma and Reduced Lung Function

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Infants that have a food allergy have an increased risk of asthma and reduced lung function later in childhood, according to a world first study published in the Lancet Child & Adolescent Health.

Food allergy affects 10% of babies and 5% of children and adolescents. The research, led by Murdoch Children’s Research Institute, found that early life food allergy was associated with an increased risk of both asthma and reduced lung growth at six years of age.

Murdoch Children’s Associate Professor Rachel Peters said this was the first study to examine the relationship between challenge-confirmed food allergy in infancy and asthma and poorer lung health later in childhood.

The Melbourne research involved 5276 infants from the HealthNuts study, who underwent skin prick testing to common food allergens, such as peanut and egg, and oral food challenges. At six years, children were followed up with further food allergy and lung function tests.

The study found by six years of age, 13.7% reported a diagnosis of asthma. Babies with a food allergy were almost four times more likely to develop asthma at six years of age, compared to children without a food allergy. The impact was greatest in children whose food allergy persisted to age six as opposed to those who had outgrown their allergy. Children with a food allergy were also more likely to have reduced lung function.

Associate Professor Peters said food allergy in infancy, whether it resolved or not, was linked to poorer respiratory outcomes in children.

“This association is concerning given reduced lung growth in childhood is associated with health problems in adulthood including respiratory and heart conditions,” she said.

“Lung development is related to a child’s height and weight and children with a food allergy can be shorter and lighter compared to their peers without an allergy. This could explain the link between food allergy and lung function. There are also similar immune responses involved in the development of both food allergy and asthma.

“The growth of infants with food allergy should be monitored. We encourage children who are avoiding foods because of their allergy to be under the care of a dietician so that nutrition can be catered for to ensure healthy growth.”

Source: Murdoch Childrens Research Institute

Most Penicillin Allergy Labels are Unnecessary – Here’s How to Fix That

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Penicillin allergy affects up to 1 in 10 Americans yet most penicillin allergy labels are in fact incorrectly applied. In addition to limiting the choice of antibiotics to prescribe, the widespread mislabelling contributes to the growing threat of antibiotic resistance. A new procedure developed by researchers at Vanderbilt University Medical Center aims to fix that.

Some 75% of penicillin allergy labels come on by age 3 due to, for example, confusion with a viral rash. The majority of these rashes were never allergic, but the labels ‘stick’ into adulthood and carry many adverse consequences.

Many low-risk patients with a penicillin allergy were able to have their penicillin allergy label removed through a simple procedure known as “direct oral challenge” as part of a world-first multi-centre randomised control trial known as the Penicillin Allergy Clinical Decision Rule (PALACE) study, the results of which were published in JAMA Internal Medicine.

In the PALACE study, investigators randomised low-risk penicillin allergic patients to two different approaches to remove their allergy label. They either underwent the current standard of care to have skin testing followed if negative by oral challenge with a penicillin or they went straight to oral challenge (“direct oral challenge”) without preceding skin testing.

“The majority of patients labelled as penicillin allergic, more than 90%, have low-risk histories, meaning they did not have a history to suggest a severe or more recent reaction to a penicillin,” said PALACE study protocol member and Vanderbilt University Medical Center principal investigator Elizabeth Phillips, MD. “We would expect more than 95% of these patients to have negative testing and be able to take penicillin in the future.”

The study, undertaken by a team of researchers from specialised centres in North America and Australia, enrolled 382 adults who were assessed using a specialized risk assessment tool called PEN-FAST. Participants were randomly assigned to receive either a direct oral penicillin challenge or the standard approach (penicillin skin testing followed by an oral challenge). The primary goal was to determine if the direct oral penicillin challenge was no worse than the standard method of skin testing followed by oral challenge which needs to be performed in an allergist’s office.

Only one patient (0.5%) in each group experienced a positive reaction to the penicillin challenge, demonstrating that the direct oral penicillin challenge performs just as well as the standard method. Importantly, there were no significant differences in adverse events between the two groups, and no serious adverse events were reported.

The findings have wide-ranging implications for patients. By accurately identifying low-risk penicillin allergy patients, health care providers can ensure appropriate antibiotic prescriptions. Patients with a documented penicillin allergy are more likely to be prescribed alternative antibiotics, known as second-line antibiotics, which are often not as effective against certain infections and may have more side effects.

“Patients with penicillin allergy are more likely to get second-line or broader spectrum antibiotics that lead to risk of antibiotic resistance and serious infections such as antibiotic-associated diarrhoea due to Clostridioides difficile, which can spread through hospitals and become a major public health problem.” Phillips said. “In the US increasingly we also have a major problem with other antibiotic-resistant ‘superbugs’ such as multi-resistant gram-negative infections, Candida auris and even a resurgence of syphilis for which penicillin is the best treatment and the only treatment that should be used in pregnancy to prevent transmission to an unborn child.

“The evidence provided by the PALACE study will change clinical practice. Many patients in the United States do not have direct access to an allergist to provide specialised testing such as skin testing. Therefore, the ability to go to direct oral challenge with a penicillin in low-risk patients which can be carried out in any observed setting will make it easier for patients in the United States to access health care to safely and effectively remove the label of penicillin allergy,” she said.

Source: Vanderbilt University Medical Center

Mast Cells Instruct the Brain to Avoid Allergens

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Mast cells functions are still something of a mystery, but scientists have now shown in mice that mast cells act as a sensor that signals the animals to avoid antigens, including harmful allergens, and thereby protect themselves from health-threatening inflammatory reactions. The findings were published in the journal Nature.

Mast cells are found primarily in tissues that separate the outside and inside worlds of the body, such as the epithelia of the gastrointestinal tract and lungs. Within the tissues, mast cells often reside near nerve endings. Mast cells are well known to persons suffering from allergies because they secrete messenger substances such as histamine, which cause annoying to health-threatening allergic symptoms. These symptoms occur when mast cells are activated by IgE class antibodies during repeated antigen contact.

“Why mast cells and IgE exist at all has not yet been conclusively explained,” says immunologist Hans-Reimer Rodewald at the at the German Cancer Research Center (DKFZ). The researcher his team have now been able to show for the first time in mice, in a combination of behavioural experiments and immunological studies, that mast cells act like a sensor that helps to avoid contact with allergens

Mast cells and IgE needed for antigen avoidance

The DKFZ researchers immunised mice with the allergen ovalbumin, a protein component of chicken egg white. They then gave the animals the free choice of preferring either normal or egg white-containing drinking water. Immunised animals avoided the egg white-enriched water, while their non-immunised conspecifics clearly preferred it. A large proportion of the immunised animals avoided the egg white-containing water already one day after immunisation, some mice even after the first sip.

However, when the scientists performed this behavioural test with mice that genetically lack mast cells, both immunised and non-immunised animals preferred the egg white-containing water. Mice genetically unable to produce IgE also showed no avoidance behaviour. Thus, both mast cells and IgE are responsible for antigen avoidance.

When the immunised mice had no choice because the egg white solution was instilled in them, the animals developed inflammation in the stomach and small intestine. “The avoidance behaviour mediated by mast cells apparently protects the animals from harmful immune reactions,” explains Thomas Plum, one of the first authors.

How do mast cells “talk” to the brain?

An important open question for the scientists was now: How can mast cells, as a component of the immune system, influence behaviour? In what ways do immune cells “talk” to the brain? The scientists examined a variety of biologically active substances released by mast cells. These include leukotrienes, pro-inflammatory messengers known to activate sensory nerves. If the researchers blocked leukotriene synthesis, the immunized mice no longer showed the same consequence in avoiding egg white. Leukotrienes therefore appear to be at least partly involved in avoidance behaviour. Further immunological and neurobiological experiments are needed in the future to identify the nerve connections through which the mast cell signal is reported to the brain.

“In the intestine, lungs or skin, immune reactions against non-infectious antigens can occur as a result of so-called barrier disorders, permeability of the tissues from the outside to the inside. In the case of allergy, we call such antigens allergens. Whether these substances are dangerous or not, it is important for the organism to avoid their further intake in order to prevent inflammatory diseases. This is an evolutionary advantage and finally a conclusive explanation of the physiological role of mast cells and IgE,” Rodewald summarizes the results.

Whether mast cells also contribute to the avoidance of harmful antigens in humans must be addressed in further studies.

Source: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)