Sustained unresponsiveness to peanut after long-term peanut epicutaneous immunotherapy (2020)

Clinical Implications•Sustained unresponsiveness to peanut, at a level that may protect from many clinical allergic reactions related to accidental exposure, has been observed in a subset of participants after 2 to 3 years of successful epicutaneous immunotherapy. •Sustained unresponsiveness to peanut, at a level that may protect from many clinical allergic reactions related to accidental exposure, has been observed in a subset of participants after 2 to 3 years of successful epicutaneous immunotherapy. Peanut allergy is a common and largely persistent food allergy with no known cure. Globally, widespread clinical trials are in progress that seek to improve the lives of children and adults with peanut allergy using desensitization to peanut via various routes, including oral, sublingual, subcutaneous, intranodal, and epicutaneous.1Sicherer S.H. Sampson H.A. Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management.J Allergy Clin Immunol. 2018; 141: 41-58Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar In addition, the US Food and Drug Administration recently granted approval of a form of peanut oral immunotherapy (OIT). Most immunotherapy trials to date have focused on efficacy during or immediately at the completion of therapy. However, the question of whether treatment effect persists once the therapy has been completed and discontinued (and while peanut avoidance otherwise continues) remains largely unclear. We sought to examine whether there was evidence of a longer-lasting effect of therapy, often described as sustained unresponsiveness (SU), and more recently as remission,2Sampson H.A. O’Mahony L. Burks A.W. Plaut M. Lack G. Akdis C.A. Mechanisms of food allergy.J Allergy Clin Immunol. 2018; 141: 11-19Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar after 2 or more years of epicutaneous peanut immunotherapy (EPIT) from a subset of participants from the Open-label follow-up Viaskin Peanut Efficacy and Safety (OLFUS-VIPES) phase 2b study.3Sampson H.A. Shreffler W.G. Yang W.H. Sussman G.L. Brown-Whitehorn T.F. Nadeau K.C. et al.Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity: a randomized clinical trial.JAMA. 2017; 318: 1798-1809Crossref PubMed Scopus (137) Google Scholar In the VIPES randomized controlled trial, the optimal dose, safety, and efficacy of 12 months of daily peanut EPIT (DBV712) in subjects with peanut allergy aged 6 to 55 years who had a baseline eliciting dose (ED) of 300 mg or less of peanut protein were assessed, followed by an open-label extension of up to 24 months on EPIT (OLFUS-VIPES).3Sampson H.A. Shreffler W.G. Yang W.H. Sussman G.L. Brown-Whitehorn T.F. Nadeau K.C. et al.Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity: a randomized clinical trial.JAMA. 2017; 318: 1798-1809Crossref PubMed Scopus (137) Google Scholar At the end of the open-label study, subjects who showed no objective symptoms (meeting stopping criteria) during a double-blind placebo-controlled food challenge (DBPCFC) at equal to or greater than a cumulative peanut dose of 1440 mg were eligible to enroll in an SU assessment. For these subjects, a further DBPCFC was conducted 2 months after cessation of peanut EPIT with continued strict peanut avoidance. As previously reported, 221 subjects enrolled in the VIPES study (of which 56 received DBV712 250 μg from randomization) and 171 enrolled in the OLFUS-VIPES extension study; within 6 months of starting the open-label extension study, all subjects were transitioned to DBV712 250 μg for the remainder of their participation.3Sampson H.A. Shreffler W.G. Yang W.H. Sussman G.L. Brown-Whitehorn T.F. Nadeau K.C. et al.Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity: a randomized clinical trial.JAMA. 2017; 318: 1798-1809Crossref PubMed Scopus (137) Google Scholar One hundred twenty-four subjects underwent a DBPCFC following a total of 36-month study duration, of which 29 (23%) had no objective symptoms to a cumulative dose of 1440 mg. This included 21 children aged 6 to 11 years and 8 adolescents/adults aged 12 to 55 years at VIPES study entry (Table I).Table ICharacteristics of participants at study entry, month 36 and 38 assessmentsCharacteristicVIPES (n = 221)Eligible for SU (n = 29)SU assessment (n = 25)Achieved SU (n = 20)Age (y),∗At VIPES entry.median (IQR)11.0 (8.0-16.0)10.0 (7.0-12.0)10.0 (7.0-11.0)10.0 (8.0-13.0)6-11 y, n (%)113 (51.1)21 (72.4)19 (76.0)14 (70.0)12-55 y, n (%)108 (48.9)8 (27.6)6 (24.0)6 (30.0)Sex: male, n (%)138 (62.4)22 (75.9)19 (76.0)17 (85.0)Initial allocation in VIPES (n) Placebo48333 50 μg44655 100 μg4111107 250 μg38975Peanut IgE (kUA/L), median (IQR) Baseline∗At VIPES entry.78.90 (17.8-217.25)19.80 (5.78-70.80)13.90 (5.09-63.80)8.09 (3.37-56.45) Month 36†Before DBPCFC.NA9.16 (3.83-44.80)8.06 (2.77-36.10)6.46 (1.45-42.40) Month 38 (SU assessment)†Before DBPCFC.NANA7.72 (2.61-33.30)6.14 (1.94-34.95)Peanut IgG4 (mg/L), median (IQR) Baseline∗At VIPES entry.0.59 (0.29-1.48)0.60 (0.23-1.05)0.60 (0.23-1.27)0.53 (0.14-1.16) Month 36†Before DBPCFC.NA2.03 (0.90-9.24)2.03 (0.85-9.24)1.62 (0.49-4.08) Month 38 (SU assessment)†Before DBPCFC.NANA1.88 (0.78-7.27)1.26 (0.56-4.35)SPT mean wheal size (mm), median (IQR)∗At VIPES entry.11.5 (9.5-14.0)11.0 (10.0-14.5)11.0 (9.5-15.0)10.3 (9.0-14.5)Baseline CRD (mg), median (IQR)∗At VIPES entry.144 (44-444)144 (144-444)144 (144-444)194 (144-444)History of asthma (%)∗At VIPES entry.58.855.260.055.0Use of epinephrine at initial DBPCFC, n (%)‡At least 1 dose of epinephrine at initial VIPES DBPCFC.93 (42.1)11 (37.9)10 (40.0)8 (40.0)IQR, Interquartile range; SPT, skin prick test.∗ At VIPES entry.† Before DBPCFC.‡ At least 1 dose of epinephrine at initial VIPES DBPCFC. Open table in a new tab IQR, Interquartile range; SPT, skin prick test. Of these 29 subjects, 25 elected to undergo the prespecified SU assessment according to the study protocol and 20 (80%) maintained desensitization to at least 1440 mg of peanut at 2-month follow-up DBPCFC (ie, had no objective symptoms to a cumulative dose of 1440 mg) (Table I and Figure 1). All 25 subjects who underwent SU assessment reached a cumulative reactive dose (CRD) of greater than or equal to 1440 mg at the month 2 SU DBPCFC, reflecting a substantial sustained improvement from baseline CRD (median, 144 mg). There was no significant change in peanut IgE (median, 8.06; 7.72 kUA/L) or peanut IgG4 (median, 2.03; 1.88 mg/L) over the 2 months off therapy at month 36 and 38, respectively, in these 25 subjects. Overall, subjects who successfully achieved SU were predominantly male and had a lower baseline median peanut IgE compared with the whole VIPES and OLFUS cohorts (Table I). SU was achieved across both age groups, and although there was a greater proportion of children who met criteria for SU assessment, of those eligible, 14 of 19 (73.7%) children aged 6 to 11 years and 6 of 6 (100%) adolescents/adults attained SU. It is difficult to determine whether there were any characteristics that discriminated between those 5 subjects who, having met the SU assessment criteria, were not able to sustain their tolerance above 1440 mg (over the 2-month cessation of therapy while avoiding peanut) compared with the 20 who achieved SU, because the numbers in each group were too small; however, it is worth noting that these subjects still reached an ED of 1000 mg (CRD of 1440 mg) at the 38-month SU DBPCFC. In addition, there were 6 subjects whose CRD decreased from month 36 to month 38, but remained greater than 1440 mg (range, 5040-6040 mg at month 36 to 2440-5040 mg at month 38), and 3 subjects whose CRD increased from month 36 to month 38 (range, 3040-3840 mg at month 36 to 4040-5040 mg at month 38) (Figure 1). Emerging murine data suggest that response to EPIT is driven primarily by regulatory T cells with no allergen-driven effector cell desensitization, suggesting both a different mechanism of action of EPIT compared with immunotherapy delivered by alternative routes, and a mechanism by which SU after cessation of immunotherapy might occur.4Bird J.A. Sanchez-Borges M. Ansotegui I.J. Ebisawa M. Ortega Martell J.A. Skin as an immune organ and clinical applications of skin-based immunotherapy.World Allergy Organ J. 2018; 11: 38Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar This is supported by hypermethylation of the Gata3 promoter and hypomethylation of the Foxp3 promoter on regulatory T cells in murine EPIT models.5Mondoulet L. Dioszeghy V. Busato F. Plaquet C. Dhelft V. Bethune K. et al.Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut-sensitized mice.Allergy. 2019; 74: 152-164Crossref PubMed Scopus (47) Google Scholar It is therefore plausible that the duration of therapeutic effect with EPIT, as suggested by animal models, may lead to a slower achievement of maximal response, but more sustained duration of desensitization, with effects continuing after therapy has ceased.4Bird J.A. Sanchez-Borges M. Ansotegui I.J. Ebisawa M. Ortega Martell J.A. Skin as an immune organ and clinical applications of skin-based immunotherapy.World Allergy Organ J. 2018; 11: 38Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar There are several limitations to the data. First, SU was assessed in only those subjects who attained desensitization after at least 24 months of EPIT to a cumulative dose of 1440 mg of peanut (∼5-6 peanut kernels). In addition, SU was defined in the protocol specifically as described above, as unresponsiveness to 1440 mg of peanut protein or greater and did not require completion of the entire DBPCFC. In contrast to SU or remission definitions used more recently, this allowed for subjects to experience CRD decreases and still meet the protocol definition of SU with a threshold of 1440 mg or higher. Tolerance to the highest DBPCFC dose was not required to achieve SU. In addition, whether subjects who attained less marked improvements in their peanut ED would have also continued to be desensitized over a similar time period off therapy, at a lower ED level, is uncertain. The baseline characteristics of subjects who were eligible for SU assessment were generally similar to those of the overall cohort, including the amount of peanut that initially triggered the allergic reaction at DBPCFC and the severity of the reaction (as measured by epinephrine usage). They differed in having a higher proportion of males and lower baseline peanut IgE. Peanut IgG4 at any time point did not distinguish between those who met eligibility criteria for the SU assessment, nor those who achieved SU (Table I). However, OLFUS-VIPES was not primarily designed to assess SU; thus, the sample size is too small to detect differences between those 20 subjects who achieved SU compared with the 5 who did not, and comparisons should be interpreted with some caution. Finally, the concept of SU itself is under some scrutiny.2Sampson H.A. O’Mahony L. Burks A.W. Plaut M. Lack G. Akdis C.A. Mechanisms of food allergy.J Allergy Clin Immunol. 2018; 141: 11-19Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Exactly what allergic reactivity, as assessed by food challenge after a relatively short period (2 months) off therapy, means for longer-term tolerance is unclear. Anecdotal follow-up reports of EPIT (where 12 of 15 patients at Children's Hospital of Philadelphia introduced peanut-containing foods on a daily basis at amounts recommended on the basis of their final DBPCFC after OLFUS-VIPES completion),6Lewis M.O. Brown-Whitehorn T.F. Cianferoni A. Rooney C. Spergel J.M. Peanut-allergic patient experiences after epicutaneous immunotherapy: peanut consumption and impact on QoL.Ann Allergy Asthma Immunol. 2019; 123: 101-103Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar and other forms of peanut immunotherapy such as OIT and OIT with adjuvant therapy, suggest that some SU possibly translates into longer-term desensitization, and in some cases ad lib peanut consumption.7Vickery B.P. Scurlock A.M. Kulis M. Steele P.H. Kamilaris J. Berglund J.P. et al.Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.J Allergy Clin Immunol. 2014; 133: 468-475Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar,8Hsiao K.C. Ponsonby A.L. Axelrad C. Pitkin S. Tang M.L.K. Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial.Lancet Child Adolesc Health. 2017; 1: 97-105Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar These reports should be viewed with cautious optimism, given the likely skewed subset of the total study populations these reports represent; indeed, it is important to recognize that SU may wane with increasing time of avoidance/off therapy, as has been demonstrated in studies of peanut OIT.9Chinthrajah R.S. Purington N. Andorf S. Long A. O’Laughlin K.L. Lyu S.C. et al.Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study.Lancet. 2019; 394: 1437-1449Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Overall, our findings support the notion that SU to peanut protein after long-term therapy with EPIT is achievable for a subset of patients with peanut allergy. Whether these effects last longer than 2 months, and whether they can be extrapolated to the wider study population, remains to be determined. Furthermore, in future studies of EPIT it will be important to robustly identify any baseline or on-therapy characteristics that may be associated with a higher propensity to short-term and longer-term SU.