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Oral Immunotherapy

Oral Immunotherapy. Wesley Burks, M.D. Professor and Chair Department of Pediatrics University of North Carolina. FACULTY DISCLOSURE. FINANCIAL INTERESTS

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Oral Immunotherapy

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  1. Oral Immunotherapy Wesley Burks, M.D. Professor and Chair Department of Pediatrics University of North Carolina

  2. FACULTY DISCLOSURE • FINANCIAL INTERESTS I have disclosed below information about all organizations and commercial interests, other than my employer, from which I or a member of my immediate family or household receive remuneration in any amount (including consulting fees, grants, honoraria, investments, etc.) or invest money which may create or be perceived as a conflict of interest. Name of Organization Nature of Relationship Allertein Minority Stockholder Dannon Co. Probiotics Advisory Board ExploraMed Consultant Intelliject Consultant Mast Cell, Inc. Minority Stockholder McNeil Nutritionals Consultant Novartis Consultant Nutricia Expert Panel Schering-Plough Consultant • RESEARCH INTERESTS I have disclosed below information about all organizations which support research projects for which I or a member of my immediate family or household serve as an investigator. Name of Organization Nature of Relationship National Institutes of Health Grantee Food Allergy and Anaphylaxis Network Grantee SHA Grantee FAI Grantee National Peanut Board Grantee Wallace Foundation Grantee

  3. Background: Food allergy • Prevalence: • 3 million school age children (3.9%) • 18% increase since 1997 Branum 2009 Pediatrics. 124:1549-55 • “evolved dependence” – changes in commensals, subclinical infections, asymptomatic carriers Rook – CEI - 2010 • 7 most common food allergens in U.S. • Milk, egg, peanut, tree nuts, shellfish, soy, wheat • Peanut allergy • Prevalence ~1% • Most common cause of anaphylaxis in children presenting to the ED • Most common cause of fatal food anaphylaxis • Standard of care • Avoidance of only foods appropriately diagnosed • Self-injectable epinephrine/antihistamines Vander Leek, J Peds 2000 Bock, J Allergy Clin Immunol 2007

  4. Food allergy and what parents hear

  5. Approaches to food allergy immunotherapy Nowak-Wegrzyn JACI March 2011

  6. Initial food allergy immunotherapy • Goals of treatment are two-fold • Clinical desensitization • tolerate more food before an accidental reaction • Eventual clinical tolerance • off treatment • Goals of research on food allergy treatment • Identify the mechanism(s) of the changes brought on by the treatment • Identify immunologic markers associated with the treatment

  7. Potential immunotherapeutic effect of heated milk and egg • ~75% of allergic children tolerate extensively heated product via OFC Regulatory T cells • Associated with reductions in: • specific IgE • PST • basophil activation • Treg activation Lemon-Mule H. JACI 2008:122:977; Nowak-Wegrzyn A. JACI 2008:122:342; Schreffler WG. JACI 2009:123:43

  8. Oral IT (OIT) swallowed with food open and blinded studies mg – gms of food Methods of immunotherapy

  9. Patterns of response to food OIT • Nowak-Wegrzyn JACI March 2011

  10. Study design: double-blind RCT peanut OIT Duke and Arkansas Maintenance 4000 mg Dose Escalation Peanut or Placebo *Food Challenge #1 (OFC 1) Desensitization Initial escalation day – 6 mg 1 peanut = 300 mg Varshney et al. JACI March 2011

  11. Study design: double-blind RCT peanut OIT Duke and Arkansas Meet criteria for assessing tolerance Maintenance 4000 mg Off OIT 1 mo Dose Escalation Peanut or Placebo *Food Challenge #1 (OFC 1) Food Challenge #2 (OFC 2) Desensitization Food Challenge #3 (OFC 3) Initial escalation day – 6 mg Tolerance 1 peanut = 300 mg Varshney et al. JACI March 2011

  12. Peanut OIT induces robust clinical desensitization and suppresses mast call activation • 25 subjects – 16 - active treatment; 9 – placebo (3 withdrew) • Any peanut-allergic subject – unless accompanied by significant hypotension • All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up Peanut OFC 1 * P=.008 Varshney et al. JACI March 2011

  13. Peanut OIT induces robust clinical desensitization and suppresses mast call activation • 25 subjects – 16 - active treatment; 9 – placebo (3 withdrew) • Any peanut-allergic subject – unless accompanied by significant hypotension • All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up Peanut SPT Peanut OFC 1 * P=.008 Varshney et al. JACI March 2011

  14. Peanut antigen specific suppressionBasophils – CD63% Hi • 4 concentrations of peanut cultured with subject’s cells at each time point – 0, 6 and 12 months (PN1, PN2, PN3, PN4) • Significant change in basophils – CD63% over time on OIT Thyagarajan, Shreffler et al. AAAAI 2009

  15. Serum levels of peanut-specific IgE and IgG4 changes with OIT treatment Peanut IgE Varshney et al. JACI March 2011 ImmunoCAP-FEIA (Phadia)

  16. Serum levels of peanut-specific IgE and IgG4 changes with OIT treatment Peanut IgE Peanut IgG4 Varshney et al. JACI March 2011 ImmunoCAP-FEIA (Phadia)

  17. Possible Mechanism(s) of OIT? • Peanut-allergic subjects on peanut OIT show a decrease in basophil responses to ex vivo peanut stimulation during the course of treatment. • Plasma - peanut-allergic subjects (n=10, median peanut-specific IgE 82.3 kU/L) and replaced with plasma from subjects receiving peanut (n=7) or placebo (n=5) OIT. • Basophil activation was assessed by measuring up-regulation of CD63. • Plasma samples from 0 and 12 months on OIT were used. • Peanut-allergic donor samples receiving plasma from subjects on peanut OIT for 12 months showed a significant decrease in basophil activation when compared to samples receiving plasma from subjects on peanut OIT for 0 months (n=28, p<0.0001) and when compared to samples receiving plasma from subjects on placebo OIT for 12 months (n=21, p<0.0001). • Basophil activation between samples receiving plasma from 0 and 12 months on placebo OIT (n=21) was not significantly different. Kulis et al. 2011

  18. Possible Mechanism(s) of OIT? • For the transferred plasma, there was an increase in peanut-specific IgG between 0 and 12 months on peanut OIT (median increase 18 mg/L to 108 mg/L; p<0.01), and no increase for placebo. • Conclusions - a factor in the plasma of subjects on peanut OIT suppressed ex vivo basophil activation in peanut-allergic subject. • Our hypothesis is that the factor is peanut-specific IgG, although further studies are needed to definitively identify it and determine its mechanism of action. Kulis et al 2011

  19. Permanent tolerance develops in some after 3 years of OIT Duke and Arkansas • 27 subjects • On OIT >36 months • Open study design • 13/27 (48%) passed food challenges to peanuts • Off treatment • These subjects remain off OIT and ingest peanut in their diets Varshney, Jones, Burks et al. AAAAI 2010

  20. Peanut OIT changes antigen-specific T regs and suppresses the TH2 response to peanut IL-5 Regulatory T cells, active treatment IL10/IL-13 ratio IL-13 Varshney et al. JACI March 2011 Kulis AAAAI 2011

  21. Peanut OIT open trial - >36 MonthsLower peanut IgE levels on entry are associated with successful completion

  22. CoFAR3 - egg OIT trial Objectives and study design Primary Objectives study the clinical effects, as well as the safety and immunologic effects, of an egg OIT protocol Primary endpoint is attainment of clinical tolerance after 2 years OIT Study Design multi-center randomized, double-blind, placebo-controlled, prospective study through 40-48 weeks Enrollment criteria (target n=55) Age 6 to 18 yrs, either sex, any race, any ethnicity with: - convincing clinical history of egg allergy - serum IgE [UniCAPTM] to egg of >5 kUA/L [<12 mo]; OR Age 5 yrs, either sex, any race, any ethnicity with: - convincing clinical history of egg allergy - serum IgE [UniCAPTM] to egg of >12 kUA/L [<12 mo] Supported by NIH-NIAID U19AI066738 and U0AI066560

  23. CoFAR3 egg OIT – permanent tolerance develops after 2 years of OIT Predictors of tolerance = change in PST baseline to yr 2 (-10.5 OIT vs. -5.5 placebo) Jones, Burks, Sampson et al CoFAR AAAAI 2011

  24. Safety of food OIT • Risk factors for unanticipated reactions: • Fever, viral infections, exercise, menses (Varshney JACI 2009) • Symptoms occur with ~15-25% of doses • Predominantly mild and oropharyngeal • <1% of doses – moderate-severe symptoms • Epinephrine use • <1% of doses • Gastrointestinal symptoms are early and limiting • Drop-out rate ~10-20%

  25. Early intervention?Oral Immunotherapy • Dr. Brian Vickery - Clinical trial to test the hypothesis that early intervention (EI) improves the efficacy of peanut OIT without adversely affecting safety or adherence. • 40 peanut-sensitized children - aged 9-36 months were enrolled within six months of their initial reaction, or if the peanut-specific IgE (psIgE) exceeded 5 kUA/L in the absence of exposure. • All subjects underwent baseline oral peanut challenge and were randomized to receive low- or high-dose OIT. • Compared demographic, safety, adherence, and immunologic data between the EI cohort and an ongoing, previously reported trial of OIT in older children (PMIT).

  26. Early intervention?Oral Immunotherapy • Subjects were approximately half as likely as PMIT subjects to have an allergic side effect (ASE) deemed “likely” or “possibly” related to OIT [RR 0.56 (95%CI 0.50-0.62), p<0.0001]. • Study termination due to ASE occurred in 3/26 (11.5%) PMIT compared to 1/40 (2.5%) EI [p=0.29]. • After one year, peanut skin test size decreased similarly in both groups, and psIgE levels remained stable. • Conclusions - early intervention with OIT may enhance safety and targets young peanut-allergic children for treatment while their psIgE levels are low.

  27. Variables in OIT studies to date

  28. Critical knowledge gaps in food OIT research • Summary - consistent results • Desensitization begins within a few days/months of treatment • – threshold goes up • Allergic side effects - primarily GI at the beginning • - viral infections, exercise • Mechanistic studies – results differ depending on length of study • Tolerance not shown in blinded studies • Patriarca et al. Aliment Pharmacol Ther 2003;17:459-65. • Meglio P, et al.. Allergy 2004;59:980-7. • Buchanan AD et al. J Allergy Clin Immunol 2007;119:199-205. • Staden U, et al. Allergy 2007;62:1261-9. • Longo G, et al. J Allergy Clin Immunol 2008;121:343-7. • Jones SM, et al. J Allergy Clin Immun 2009. • Skripak JM et al. J Allergy Clin Immunol 2008;122:1154-60. • Blumchen K et al. J Allergy Clin Immunol 2010;126:83-91. • Varshney P et al. J Allergy Clin Immunol March 2011 (In Press). • Jones SJ, Burks AW, Sampson HA et al – CoFAR 2011

  29. SPT mean wheal size decreased by 6 mo Further decreased to 24 mo Basophil activation decreased by 4 mo Further decreased to 24 mo Specific-IgE increased by 2-3 mo Between 6-18 mo – variable, similar to baseline or decreased. By 24 mo is decreased Specific-IgG4 increased by 2-3 mo Continues to increase to 24 mo, then begins to decline Effector Cells Specific-IgE Specific-IgG4 0 2 3 4 6 9 12 18 24 36 Time on OIT (months)

  30. Immunotherapy for food allergy – the future ? Goal: development of initial active treatment for food allergy OIT/SLIT – still investigational Studies needed to understand possible clinical benefit and mechanism randomized, blinded controlled trials – in process now optimizing pharmacokinetics targeting appropriate population(s) Determine mechanism of action of OIT/SLIT Basophils/mast cells, humoral, cellular Determine if food IT induces Desensitization without/and clinical tolerance Is desensitization alone worthwhile? Longer term goal: next-generation of therapy to enhance the development of immune tolerance

  31. Thanks Grant support Food Allergy and Anaphylaxis Network, Food Allergy Project, Food Allergy Initiative, Gerber Foundation, NIHR01 – AI, NIHR01-NCCAM, NIH 1 UL1 RR024128-01 (DCRU), Doris and Frank Robins Family, National Peanut Board, NIAID-CoFAR Team Physicians - Stacie Jones (AR), Joe Roberts, Brian Vickery, Michael Land, Wayne Shreffler (Harvard), Hugh Sampson (Mt. Sinai), CoFAR Team Study coordinators - Pam Steele, Jan Kamilaris, Alison Edie, Janie Hainline Fellows - Amy Scurlock, Arianna Buchanan, Krisha Palmer, Todd Green, Alison Hofmann, Pooja Varshney, Ananth Thyagarajan, Drew Bird, Edwin Kim, Stacy Chin, Stephen Boden Laboratory - Mike Kulis, PhD, Xiaoping Zhong, MD/PhD, Laurent Pons, PhD, Herman Staats, PhD DCRU/Rankin staff

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