Immunotherapy for kids' food allergies is taking baby steps

SAN ANTONIO – Oral and sublingual immunotherapy strategies aren’t yet ready for prime time, but they continue to show promise for inducing tolerance in children with food allergies.

Oral immunotherapy

Preliminary findings from a study of low-dose oral immunotherapy (OIT) for peanut allergy, for example, suggest this approach is an effective early-intervention strategy, Dr. Brian Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In a randomized, controlled trial involving 49 peanut-sensitized children aged 9-36 months, both low- and high-dose immunotherapy resulted in a significant reduction in both peanut-specific IgE (psIgE) and skin prick test values after a median of 19 treatments, said Dr. Vickery, who is a pediatric allergist and immunologist at the University of North Carolina at Chapel Hill.

The degree of change was similar in those treated with low-dose and high-dose oral immunotherapy. The low dose slope coefficient for psIgE was -2.53 for the low dose group, compared with –1.63 for the high-dose group; and the low dose slope coefficient for the skin prick test was –0.007, compared with –0.009 for the high-dose group, he said.

Of eight subjects who met the criteria for tolerance evaluation as of the time of Dr. Vickery’s presentation, seven had successfully achieved tolerance and now eat peanut ad lib, he noted.

Study subjects were enrolled within 6 months of their index reaction or demonstration of psIgE greater than 5 kUA/L. After randomization to the low- or high-dose treatment group, they underwent serial analysis of immune responses. After at least 1 year of maintenance oral immunotherapy, clinical tolerance was assessed using a double-blinded placebo-controlled oral food challenge based on predefined clinical and immunologic benchmarks.

The findings are preliminary but suggest that early-intervention peanut oral immunotherapy is a feasible strategy. In addition, low-dose oral immunotherapy – using a 10-fold lower dose of peanut protein (the equivalent of about 1 vs. 10 peanuts comprised the maintenance doses in the low- and high-dose groups, respectively) may be sufficiently immunomodulatory in young children with newly diagnosed peanut allergy, Dr. Vickery said during a press briefing at the meeting.

Furthermore, the findings suggest that such an approach is technically possible in that young children can be recruited and treated in this manner, he noted.

Dr. Robert A. Wood, who is chief of the division of allergy and immunology at Hopkins Children’s Center at Johns Hopkins University, Baltimore, and who also presented oral immunotherapy data, noted during the press briefing that the approach used in this study "is sort of seizing on the opportunity that maybe kids early in life, when their allergy is less established, may be more amenable to treatment."

Peanut allergy that manifests in early childhood typically intensifies over 5-10 years, he explained.

The findings, however, are very preliminary.

"In order for us to really understand the impact of these two doses, we will need to assess all of the endpoints in all of the subjects who are currently enrolled, and then unblind the study at the end of it, and do an assessment to really understand whether low or high dose therapy was effective," Dr. Vickery said.

Sublingual immunotherapy

Sublingual immunotherapy (SLIT) is another promising intervention for food allergic children, according to findings from a study presented by Dr. A. Wesley Burks, who is chair of pediatrics at the University of North Carolina at Chapel Hill and physician in chief of N.C. Children’s Hospital, also in Chapel Hill.

Interim data from that study of 44 patients showed that after 36 months of dosing, peanut SLIT–induced clinical tolerance with concurrent changes in skin testing and peanut-specific immunoglobulin levels.

Of 11 patients who completed 36 months of dosing, 6 passed a peanut oral food challenge to 5,000 mg of peanut protein. The remaining five patients ingested a median of 3,750 mg of peanut protein. After SLIT discontinuation for 1 month, five of six passed an identical oral food challenge, suggesting clinical tolerance.

Children in this study were aged 2-11 years. All received open-label peanut SLIT with a daily maintenance dose of 2 mg of peanut protein, Dr. Burks said.

The findings do not say anything about long-term efficacy of SLIT, but they do show that tolerance can be induced, at least in the short term, Dr. Burke said.

Predictors of tolerance induction

Another study presented by Dr. Burke shed some light on factors associated with induction of tolerance, namely basophil hyporesponsiveness and a low peanut IgE:IgG4 ratio.

In that study of 12 patients who received SLIT and 27 who received OIT, 5 (41.7%) and 18 (66.7%), respectively, developed tolerance following immunotherapy. In the SLIT subjects, basophil responses were significantly lower among those who developed tolerance than among those who did not. This was true for each of the 4 log-fold dilutions of peanut antigen used in the assay, Dr. Burks said.

The vast majority of tolerant subjects (91.3%) had a peanut-IgE:IgG4 ratio below 0.92, compared with only 20% of nontolerant subjects.

All subjects underwent double-blind placebo-controlled food challenges to assess desensitization while they were on daily immunotherapy, and those passing the challenge ceased daily therapy and avoided all peanut products for 4 weeks. At 4 weeks, a second food challenge was administered.

The findings suggest that basophil suppression and the balance of antigen-specific IgE and IgG4 may be important in the development of tolerance following peanut immunotherapy, Dr. Burks said.

Long-term immunotherapy outcomes

One missing piece of the immunotherapy puzzle are data on long-term outcomes, as most studies report only 1-2 year outcomes. Another study presented by Dr. Wood, however, takes a step toward filling the gap – with underwhelming results.

The small study looked at long-term outcomes following milk oral immunotherapy in children, and showed that at 4.5 year follow-up, only about 25% of 32 patients were tolerating at least one serving of milk daily and 25% were consuming only trace amounts or were on strict avoidance mainly because of reactions. About 40% of patients were having frequent reactions to milk, 20% had required epinephrine for reactions, and 30% had experienced systemic reactions.

The patients were treated in two studies during 2006 and 2007 with a dose escalation to 500 mg of milk protein over about 8 weeks, followed by 3 months of maintenance dosing. Dietary milk was introduced in amounts ranging from 500 to 4,000 mg daily based on the results of a double-blind placebo-controlled food challenge.

Of note, one subject who passed a 16-g challenge without symptoms went on to become reactive again and now consumes only minimal milk, Dr. Wood said

In fact, one of the surprising things in this study was that some of the more dramatic failures long-term were in children who had achieved success in the initial studies.

These were children who "looked like absolute successes" at the end of the study, because there were tolerating large amounts of milk, he said.

"We really thought – and we hesitate to use the word "cure" – that they were about as close to cured as we could really imagine. And now, 3-5 years later, they are having anaphylactic reactions and are back on strict milk avoidance," he said.

As a result, the excitement following the initial studies has waned somewhat.

"We had a very high degree of optimism. I’m not saying we lost that optimism, but it is certainly tempered a bit by looking at where these kids now stand 3-5 years out," he said, concluding that more research with respect to long-term outcomes of food oral immunotherapy is needed, including investigation of whether longer treatment would improve outcomes, and whether certain factors can predict response and failure.

"The most important message is that this sort of adds another caveat about why we need more research before we can bring this out to our patient population. A message that I think all of us who are doing this research have come to agree upon is that we need long-term follow-up and that letting these kids go at the end of the study is not the end of the story."

Taken together, the findings of these studies underscore a need for more research regarding SLIT vs. OIT, higher vs. lower dosing, and treatment duration, as well as long-term follow-up, the investigators agreed.

"The message is that what we are doing so far is very encouraging, but it’s not the final answer. Where we need to be to bring this out to the general public is several steps beyond where we are now," Dr. Wood said.

The investigators reported having no disclosures.

SAN ANTONIO – Oral and sublingual immunotherapy strategies aren’t yet ready for prime time, but they continue to show promise for inducing tolerance in children with food allergies.

Oral immunotherapy

Preliminary findings from a study of low-dose oral immunotherapy (OIT) for peanut allergy, for example, suggest this approach is an effective early-intervention strategy, Dr. Brian Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In a randomized, controlled trial involving 49 peanut-sensitized children aged 9-36 months, both low- and high-dose immunotherapy resulted in a significant reduction in both peanut-specific IgE (psIgE) and skin prick test values after a median of 19 treatments, said Dr. Vickery, who is a pediatric allergist and immunologist at the University of North Carolina at Chapel Hill.

The degree of change was similar in those treated with low-dose and high-dose oral immunotherapy. The low dose slope coefficient for psIgE was -2.53 for the low dose group, compared with –1.63 for the high-dose group; and the low dose slope coefficient for the skin prick test was –0.007, compared with –0.009 for the high-dose group, he said.

Of eight subjects who met the criteria for tolerance evaluation as of the time of Dr. Vickery’s presentation, seven had successfully achieved tolerance and now eat peanut ad lib, he noted.

Study subjects were enrolled within 6 months of their index reaction or demonstration of psIgE greater than 5 kUA/L. After randomization to the low- or high-dose treatment group, they underwent serial analysis of immune responses. After at least 1 year of maintenance oral immunotherapy, clinical tolerance was assessed using a double-blinded placebo-controlled oral food challenge based on predefined clinical and immunologic benchmarks.

The findings are preliminary but suggest that early-intervention peanut oral immunotherapy is a feasible strategy. In addition, low-dose oral immunotherapy – using a 10-fold lower dose of peanut protein (the equivalent of about 1 vs. 10 peanuts comprised the maintenance doses in the low- and high-dose groups, respectively) may be sufficiently immunomodulatory in young children with newly diagnosed peanut allergy, Dr. Vickery said during a press briefing at the meeting.

Furthermore, the findings suggest that such an approach is technically possible in that young children can be recruited and treated in this manner, he noted.

Dr. Robert A. Wood, who is chief of the division of allergy and immunology at Hopkins Children’s Center at Johns Hopkins University, Baltimore, and who also presented oral immunotherapy data, noted during the press briefing that the approach used in this study "is sort of seizing on the opportunity that maybe kids early in life, when their allergy is less established, may be more amenable to treatment."

Peanut allergy that manifests in early childhood typically intensifies over 5-10 years, he explained.

The findings, however, are very preliminary.

"In order for us to really understand the impact of these two doses, we will need to assess all of the endpoints in all of the subjects who are currently enrolled, and then unblind the study at the end of it, and do an assessment to really understand whether low or high dose therapy was effective," Dr. Vickery said.

Sublingual immunotherapy

Sublingual immunotherapy (SLIT) is another promising intervention for food allergic children, according to findings from a study presented by Dr. A. Wesley Burks, who is chair of pediatrics at the University of North Carolina at Chapel Hill and physician in chief of N.C. Children’s Hospital, also in Chapel Hill.

Interim data from that study of 44 patients showed that after 36 months of dosing, peanut SLIT–induced clinical tolerance with concurrent changes in skin testing and peanut-specific immunoglobulin levels.

Of 11 patients who completed 36 months of dosing, 6 passed a peanut oral food challenge to 5,000 mg of peanut protein. The remaining five patients ingested a median of 3,750 mg of peanut protein. After SLIT discontinuation for 1 month, five of six passed an identical oral food challenge, suggesting clinical tolerance.

Children in this study were aged 2-11 years. All received open-label peanut SLIT with a daily maintenance dose of 2 mg of peanut protein, Dr. Burks said.

The findings do not say anything about long-term efficacy of SLIT, but they do show that tolerance can be induced, at least in the short term, Dr. Burke said.

Predictors of tolerance induction

Another study presented by Dr. Burke shed some light on factors associated with induction of tolerance, namely basophil hyporesponsiveness and a low peanut IgE:IgG4 ratio.

In that study of 12 patients who received SLIT and 27 who received OIT, 5 (41.7%) and 18 (66.7%), respectively, developed tolerance following immunotherapy. In the SLIT subjects, basophil responses were significantly lower among those who developed tolerance than among those who did not. This was true for each of the 4 log-fold dilutions of peanut antigen used in the assay, Dr. Burks said.

The vast majority of tolerant subjects (91.3%) had a peanut-IgE:IgG4 ratio below 0.92, compared with only 20% of nontolerant subjects.

All subjects underwent double-blind placebo-controlled food challenges to assess desensitization while they were on daily immunotherapy, and those passing the challenge ceased daily therapy and avoided all peanut products for 4 weeks. At 4 weeks, a second food challenge was administered.

The findings suggest that basophil suppression and the balance of antigen-specific IgE and IgG4 may be important in the development of tolerance following peanut immunotherapy, Dr. Burks said.

Long-term immunotherapy outcomes

One missing piece of the immunotherapy puzzle are data on long-term outcomes, as most studies report only 1-2 year outcomes. Another study presented by Dr. Wood, however, takes a step toward filling the gap – with underwhelming results.

The small study looked at long-term outcomes following milk oral immunotherapy in children, and showed that at 4.5 year follow-up, only about 25% of 32 patients were tolerating at least one serving of milk daily and 25% were consuming only trace amounts or were on strict avoidance mainly because of reactions. About 40% of patients were having frequent reactions to milk, 20% had required epinephrine for reactions, and 30% had experienced systemic reactions.

The patients were treated in two studies during 2006 and 2007 with a dose escalation to 500 mg of milk protein over about 8 weeks, followed by 3 months of maintenance dosing. Dietary milk was introduced in amounts ranging from 500 to 4,000 mg daily based on the results of a double-blind placebo-controlled food challenge.

Of note, one subject who passed a 16-g challenge without symptoms went on to become reactive again and now consumes only minimal milk, Dr. Wood said

In fact, one of the surprising things in this study was that some of the more dramatic failures long-term were in children who had achieved success in the initial studies.

These were children who "looked like absolute successes" at the end of the study, because there were tolerating large amounts of milk, he said.

"We really thought – and we hesitate to use the word "cure" – that they were about as close to cured as we could really imagine. And now, 3-5 years later, they are having anaphylactic reactions and are back on strict milk avoidance," he said.

As a result, the excitement following the initial studies has waned somewhat.

"We had a very high degree of optimism. I’m not saying we lost that optimism, but it is certainly tempered a bit by looking at where these kids now stand 3-5 years out," he said, concluding that more research with respect to long-term outcomes of food oral immunotherapy is needed, including investigation of whether longer treatment would improve outcomes, and whether certain factors can predict response and failure.

"The most important message is that this sort of adds another caveat about why we need more research before we can bring this out to our patient population. A message that I think all of us who are doing this research have come to agree upon is that we need long-term follow-up and that letting these kids go at the end of the study is not the end of the story."

Taken together, the findings of these studies underscore a need for more research regarding SLIT vs. OIT, higher vs. lower dosing, and treatment duration, as well as long-term follow-up, the investigators agreed.

"The message is that what we are doing so far is very encouraging, but it’s not the final answer. Where we need to be to bring this out to the general public is several steps beyond where we are now," Dr. Wood said.

The investigators reported having no disclosures.

SAN ANTONIO – Oral and sublingual immunotherapy strategies aren’t yet ready for prime time, but they continue to show promise for inducing tolerance in children with food allergies.

Oral immunotherapy

Preliminary findings from a study of low-dose oral immunotherapy (OIT) for peanut allergy, for example, suggest this approach is an effective early-intervention strategy, Dr. Brian Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In a randomized, controlled trial involving 49 peanut-sensitized children aged 9-36 months, both low- and high-dose immunotherapy resulted in a significant reduction in both peanut-specific IgE (psIgE) and skin prick test values after a median of 19 treatments, said Dr. Vickery, who is a pediatric allergist and immunologist at the University of North Carolina at Chapel Hill.

The degree of change was similar in those treated with low-dose and high-dose oral immunotherapy. The low dose slope coefficient for psIgE was -2.53 for the low dose group, compared with –1.63 for the high-dose group; and the low dose slope coefficient for the skin prick test was –0.007, compared with –0.009 for the high-dose group, he said.

Of eight subjects who met the criteria for tolerance evaluation as of the time of Dr. Vickery’s presentation, seven had successfully achieved tolerance and now eat peanut ad lib, he noted.

Study subjects were enrolled within 6 months of their index reaction or demonstration of psIgE greater than 5 kUA/L. After randomization to the low- or high-dose treatment group, they underwent serial analysis of immune responses. After at least 1 year of maintenance oral immunotherapy, clinical tolerance was assessed using a double-blinded placebo-controlled oral food challenge based on predefined clinical and immunologic benchmarks.

The findings are preliminary but suggest that early-intervention peanut oral immunotherapy is a feasible strategy. In addition, low-dose oral immunotherapy – using a 10-fold lower dose of peanut protein (the equivalent of about 1 vs. 10 peanuts comprised the maintenance doses in the low- and high-dose groups, respectively) may be sufficiently immunomodulatory in young children with newly diagnosed peanut allergy, Dr. Vickery said during a press briefing at the meeting.

Furthermore, the findings suggest that such an approach is technically possible in that young children can be recruited and treated in this manner, he noted.

Dr. Robert A. Wood, who is chief of the division of allergy and immunology at Hopkins Children’s Center at Johns Hopkins University, Baltimore, and who also presented oral immunotherapy data, noted during the press briefing that the approach used in this study "is sort of seizing on the opportunity that maybe kids early in life, when their allergy is less established, may be more amenable to treatment."

Peanut allergy that manifests in early childhood typically intensifies over 5-10 years, he explained.

The findings, however, are very preliminary.

"In order for us to really understand the impact of these two doses, we will need to assess all of the endpoints in all of the subjects who are currently enrolled, and then unblind the study at the end of it, and do an assessment to really understand whether low or high dose therapy was effective," Dr. Vickery said.

Sublingual immunotherapy

Sublingual immunotherapy (SLIT) is another promising intervention for food allergic children, according to findings from a study presented by Dr. A. Wesley Burks, who is chair of pediatrics at the University of North Carolina at Chapel Hill and physician in chief of N.C. Children’s Hospital, also in Chapel Hill.

Interim data from that study of 44 patients showed that after 36 months of dosing, peanut SLIT–induced clinical tolerance with concurrent changes in skin testing and peanut-specific immunoglobulin levels.

Of 11 patients who completed 36 months of dosing, 6 passed a peanut oral food challenge to 5,000 mg of peanut protein. The remaining five patients ingested a median of 3,750 mg of peanut protein. After SLIT discontinuation for 1 month, five of six passed an identical oral food challenge, suggesting clinical tolerance.

Children in this study were aged 2-11 years. All received open-label peanut SLIT with a daily maintenance dose of 2 mg of peanut protein, Dr. Burks said.

The findings do not say anything about long-term efficacy of SLIT, but they do show that tolerance can be induced, at least in the short term, Dr. Burke said.

Predictors of tolerance induction

Another study presented by Dr. Burke shed some light on factors associated with induction of tolerance, namely basophil hyporesponsiveness and a low peanut IgE:IgG4 ratio.

In that study of 12 patients who received SLIT and 27 who received OIT, 5 (41.7%) and 18 (66.7%), respectively, developed tolerance following immunotherapy. In the SLIT subjects, basophil responses were significantly lower among those who developed tolerance than among those who did not. This was true for each of the 4 log-fold dilutions of peanut antigen used in the assay, Dr. Burks said.

The vast majority of tolerant subjects (91.3%) had a peanut-IgE:IgG4 ratio below 0.92, compared with only 20% of nontolerant subjects.

All subjects underwent double-blind placebo-controlled food challenges to assess desensitization while they were on daily immunotherapy, and those passing the challenge ceased daily therapy and avoided all peanut products for 4 weeks. At 4 weeks, a second food challenge was administered.

The findings suggest that basophil suppression and the balance of antigen-specific IgE and IgG4 may be important in the development of tolerance following peanut immunotherapy, Dr. Burks said.

Long-term immunotherapy outcomes

One missing piece of the immunotherapy puzzle are data on long-term outcomes, as most studies report only 1-2 year outcomes. Another study presented by Dr. Wood, however, takes a step toward filling the gap – with underwhelming results.

The small study looked at long-term outcomes following milk oral immunotherapy in children, and showed that at 4.5 year follow-up, only about 25% of 32 patients were tolerating at least one serving of milk daily and 25% were consuming only trace amounts or were on strict avoidance mainly because of reactions. About 40% of patients were having frequent reactions to milk, 20% had required epinephrine for reactions, and 30% had experienced systemic reactions.

The patients were treated in two studies during 2006 and 2007 with a dose escalation to 500 mg of milk protein over about 8 weeks, followed by 3 months of maintenance dosing. Dietary milk was introduced in amounts ranging from 500 to 4,000 mg daily based on the results of a double-blind placebo-controlled food challenge.

Of note, one subject who passed a 16-g challenge without symptoms went on to become reactive again and now consumes only minimal milk, Dr. Wood said

In fact, one of the surprising things in this study was that some of the more dramatic failures long-term were in children who had achieved success in the initial studies.

These were children who "looked like absolute successes" at the end of the study, because there were tolerating large amounts of milk, he said.

"We really thought – and we hesitate to use the word "cure" – that they were about as close to cured as we could really imagine. And now, 3-5 years later, they are having anaphylactic reactions and are back on strict milk avoidance," he said.

As a result, the excitement following the initial studies has waned somewhat.

"We had a very high degree of optimism. I’m not saying we lost that optimism, but it is certainly tempered a bit by looking at where these kids now stand 3-5 years out," he said, concluding that more research with respect to long-term outcomes of food oral immunotherapy is needed, including investigation of whether longer treatment would improve outcomes, and whether certain factors can predict response and failure.

"The most important message is that this sort of adds another caveat about why we need more research before we can bring this out to our patient population. A message that I think all of us who are doing this research have come to agree upon is that we need long-term follow-up and that letting these kids go at the end of the study is not the end of the story."

Taken together, the findings of these studies underscore a need for more research regarding SLIT vs. OIT, higher vs. lower dosing, and treatment duration, as well as long-term follow-up, the investigators agreed.

"The message is that what we are doing so far is very encouraging, but it’s not the final answer. Where we need to be to bring this out to the general public is several steps beyond where we are now," Dr. Wood said.

The investigators reported having no disclosures.