Itisestimatedthatasmanyas30%ofpeoplewithfoodallergy(FA)sufferfrommultipleFAs.Theimmune mechanisms underlying different clinical outcomes of oral immunotherapy (OIT) are not well understood, particularly in multi-food allergic individuals, and it is not clear to what extent combining OIT with other immunomodulatingtherapiesmightimprovethesafetyorefficacyofOITinFA,orthedurabilityoffavorable clinicaloutcomes.ThereisanunmetneedfornewtherapiesinFA,sinceOITisassociatedwithrefractoryor fail-to-treatpopulations,likelyduetoanumberofcellularandmolecularendotypesandclinicalphenotypes. BecausethecytokinesIL-4andIL-13areimportantimmunedriversofFAthatactupstreamofIgEingenerating anallergicresponse,toaddressthesechallenges,ourapproachistoconductapilot,phase2,multiplefood allergenOIT(mOIT)studytocomparethesafety,efficacyanddurabilityofmOITcombinedwiththeanti-IL- 4R? antibody dupilumab (DmO) vs. mOIT alone, and vs. mOIT combined with the anti-IgE antibody, omalizumab(OmO).Wehypothesizethatsuchcombinationtherapycouldimprovethesafety,efficacyand/or durabilityofmOITinmulti-FApatients.WealsohypothesizethatDmO,butnotOmO,willimprovesustained unresponsivenessoutcomesvs.mOITalone,duetotheeffectsofdupilumabontheactionsofIL-4andIL-13. Our study will provide samples at screening, throughout OIT, and long-term after OIT, for key bioassays in Projects 2 (B cells), 3 (T cells) and 4 (basophils). Our study thus offers an arguably unique opportunity to achieve our overall objective: creating a comprehensive dataset of the clinical and immune monitoring outcomesofOITprotocolstobetterunderstandmechanismsofFAandtoimprovethesafetyandefficacyof FAtherapy.
Our specificaims areto:1)TestwhethertreatmentwithmOITcombinedwitheitheromalizumab ordupilumabvs.mOITaloneresultsinahigherproportionofparticipantsbeingabletopassafoodchallenge atweek24(primaryendpoint)andafteraperiodofallergenwithdrawalatweek30(asecondaryendpoint);? 2)DeterminewhethertheseOITprotocolshavelastingeffectsontheefficacyandsafetyofthesetreatments, andonchangesinthesubjects'immuneresponsesthatwereinducedbysuchtreatments;?and3)ObtainGI biopsiesofparticipantstopermitadetailedanalysisofimmunecellsandtheirproductsinGItissues,atentry intothetrialtoidentifyfeaturesassociatedwithFAatthediseasesite,andoverthecourseofOITtoevaluate whetherandhowthesefeaturesmightchange.Project1willbethefirststudytoevaluateandcompareeach immunomodulatingdrugcombinedwithmOITvs.mOITalone:thenoveltyofthestudydesigncombinedwith detailedmechanisticstudiesofbloodandGIbiopsieswillpermitustoadvancethemechanisticunderstanding ofFAandOIT,andtoestablishmoreeffectiveandsaferapproachestoFAtreatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104209-07
Application #
9851794
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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