Nonallergen-specific Treatments for Food Allergy

Jay A. Lieberman, MD; Julie Wang, MD

Curr Opin Allergy Clin Immunol. 2012;12(3):293-301.

Anti-IgE Therapy

The rationale behind the use of anti-IgE therapy for food allergy is no different than for its use in other atopic conditions. By decreasing free serum IgE levels and downregulating the expression of the high-affinity IgE receptor, anti-IgE therapy should theoretically decrease IgE-dependent mast cell and basophil responses to ingested allergen as it does to inhaled allergens.

Initial Study

Data for the use of anti-IgE therapy in food allergy were first reported in 2003.^[27] In the initial trial, 84 peanut-allergic individuals, 12–64 years of age, were randomized to receive one of three doses (150, 300, and 450 mg) of a humanized, monoclonal anti-IgE antibody known as TNX-901 (also known as Hu-901) or placebo. All individuals had an entry double-blinded peanut challenge and a posttreatment open peanut challenge 2–4 weeks after completion of therapy. Treatment with TNX-901 increased the eliciting threshold dose of peanut at the posttreatment challenge in a dose-dependent manner; however, only the highest dose (450 mg) produced a statistically significant difference over placebo. Furthermore, the efficacy of this treatment was not uniform for individuals; although 25% of patients were able to tolerate over 20 peanuts following therapy, another 25% failed to develop any improvement in tolerance.

Omalizumab and Food Allergy

The promising results of the initial anti-IgE therapy in food allergy led to a double-blind trial of the currently commercially available anti-IgE antibody, omalizumab (Xolair; Genentech, South San Francisco, CA), in peanut allergy.^[28••] In this trial, peanut allergic patients (6–75 years old) were randomized to receive either omalizumab or placebo in a 2 : 1 ratio. Unfortunately, this study was cut short due to the severity of two anaphylactic reactions during the baseline, qualifying peanut challenges (prior to the administration of any study drug). Only 14 individuals completed the trial up to that point (nine in the active arm and five in the placebo arm). Given that the study was initially powered to enroll 150 individuals, it is not surprising that the data did not reach statistical significance. However, as with the initial trial of anti-IgE therapy, omalizumab showed promising results suggesting that anti-IgE can increase the threshold dose required to elicit a reaction. When comparing the baseline tolerable peanut dose to the post-24 week treatment tolerable dose, there was a trend of increased peanut tolerability in the omalizumab-treated individuals compared with the placebo-treated individuals (P = 0.054). In addition,44%of the omalizumab-treated individuals were able to tolerate the goal dose of 1 g of peanut protein after 24 weeks of treatment compared with only one individual in the placebo-treated arm. Thus, it is possible that anti-IgE therapy could decrease the chances of an allergic reaction due to accidental ingestion, but it is unclear whether it could lead to tolerance.

Future Directions

Just as omalizumab has been used as an adjunctive therapy to increase efficacy and decrease adverse reactions with immunotherapy for respiratory allergy,^[29] there may be a role for its use as an adjunct to immunotherapy for food allergy. Although there are several promising reports on oral immunotherapy (OIT) for food allergy, this treatment is not without risks. Difficulties with oral and gastrointestinal side effects, as well as systemic allergic reactions have been reported with OIT.^[30] The addition of anti-IgE therapy to food immunotherapy may accelerate the desensitization process while minimizing adverse effects.

Preliminary results have now been published for one such study examining the use of omalizumab in a rush protocol of milk OIT.^[31•] In this brief communication, the authors showed that treatment with omalizumab 7–11 weeks prior to initiating milk OIT allowed nine of the 11 enrolled individuals to tolerate the 1-day rush desensitization protocol going from 0.1 to 1000mg of milk protein. This was a pilot study, lacking a placebo group and baseline double-blinded milk challenge; however, it points to the potential use of omalizumab with food OIT, and there are now ongoing trials currently assessing the use of anti-IgE with OIT to various foods (Clinicaltrials.gov identifiers: NCT01157117,NCT00932282,NCT01290913).

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Table 1. Summary of selected allergen nonspecific therapy publications
Therapy type	Publication	Model	Study and treatment Goal	Findings and summary
Chinese Herbal Therapy	Li et al. 2001¹⁷	Mouse; peanut	FAHF-1; treatment	Mice in active group had:
				Decreased anaphylaxis score
				Lower plasma histamine levels
				Lower numbers of degranulated tissue mast cells
				Lower peanut sIgE
	Srivastava et al. ¹⁹	Mouse; peanut	FAHF-2; treatment	Mice in active group had:
				Decreased anaphylaxis scores 5 weeks post treatment
				Lower plasma histamine levels
				Decreased vascular leakage
				Decreased peanut sIgE
				Increased peanut sIgG2a
	Srivastava et al. ²⁰	Mouse; peanut	FAHF-2; treatment	Mice in active group had:
				Decreased anaphylaxis scores 26 weeks post treatment
				Effect appeared IFN-γ dependent in part
	Song et al. ²²	Mouse; peanut	FAHF-2; treatment	Mice in active group had:
				Decreased anaphylaxis scores 4 weeks posttherapy
				Decreased numbers peripheral blood basophils
				Decreased numbers of peritoneal mast cells
				Decreased expression of FcεRI on peritoneal mast cells
	Wang et al. ^24•	Human; multiple foods	FAHF-2; RDBPC; treatment; phase I dosing study	Initial safety trial in humans:
				Minimal side effects seen after one week of treatment
	Patil et al. ²⁵	Human; multiple foods	FAHF-2; RDBPC; treatment; extended phase I study	Extended safety trial:
				Only reported adverse event after 6 months of treatment in 14 patients
				Decreased percentage of CD63⁺ basophils in peripheral blood upon antigen stimulation after 6 months of treatment
Anti-IgE Therapy	Leung et al. ²⁷	Human; peanut	TNX-901; RDBPC; treatment dosing study	The highest dose (450 mg) given every weeks for four doses significantly increased peanut threshold doses over baseline as compared with placebo
	Sampson et al. ^28••	Human; peanut	Omalizumab; RDBPC; treatment	Limited data suggested trend toward increased peanut threshold dose over baseline in those treated with omalizumab as compared with placebo
				Study cut short due to anaphylaxis during entry (pretreatment) double-blind peanut challenge
Probiotics	Schiavi et al. ⁴⁰	Mouse; shrimp	Probiotic mixture of 8 strains; treatment	Mice in active group had:
				Decreased anaphylaxis score
				Lower fecal histamine levels
				Lower levels of jejunal Th2 cytokines
	Hol et al. ⁴³	Human; infants younger than 6 month with milk allergy	Probiotic mixture of 2 strains; RDBPC; treatment	No difference in development of tolerance in treatment versus placebo groups after 6 and 12 months
				No difference in egg or soy sensitization rates in the two treatment groups
	Kim et al. ³⁴	Human; pregnant women with family history of allergic disease	Probiotic mixure of 3 strains; RDBPC; prophylaxis	No difference in food sensitization or probable food allergy in treatment versus placebo groups after 1 year
	Niers et al. ³⁵	Human; pregnant women with family history of allergic disease	Probiotic mixure of 3 strains; RDBPC; prophylaxis	No difference in food sensitization in treatment versus placebo after 1 and 2 years
	Boyle et al. ³²	Human; pregnant women with family history of allergic disease	Probiotic of single strain; RDBPC; prophylaxis	No difference in food sensitization in treatment versus placebo after 1 year
Engineered Lactic Acid Bacteria	Frossard et al. ⁵⁰	Mouse; milk (β-lac)	IL-10 secreting L. lactis; prophylaxis	Mice pretreated with IL-10 secreting L. lactis had lower anaphylaxis scores upon challenge with β-lac
Helminth Therapy	Bashir et al. ⁵⁶	Mouse; peanut	H polygyrus infected mice; prophylaxis	H polygyrus infection prior to sensitization led to:
				Decreased anaphylaxis scores
				Lower plasma histamine levels
				Lower peanut sIgE
				Effects were attenuated with anti-IL-10

FAHF, food allergy herbal formula; IFN-g, interferon gamma; IL, interleukin; RDBPC, randomized double-blind placebo-controlled trial; sIgE, specific IgE.

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