Jeffrey R. Stokes

Immunotherapy: What lies beyond

Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy.

Future forms of immunotherapy

Allergic respiratory diseases affect approximately 15% of the US population. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. During the first 75 years, conventional subcutaneous immunotherapy did not change much. However, the last 25 years has seen substantial growth in the development of alternatives to conventional subcutaneous immunotherapy. The addition of omalizumab, an anti-IgE mAb, to immunotherapy offers the potential for increased safety and efficacy. Activation of the innate immune system through Toll-like receptor agonists with and without specific allergens appears to improve the immunologic responses and clinical outcomes in patients with allergic diseases. The use of chemically altered allergens, allergoids, recombinant allergens, and relevant T-cell epitope peptides are all approaches that have yielded positive results. Finally, alternative modes of delivery hold promise, with sublingual immunotherapy rapidly approaching mainstream use in many countries. One thing is clear: the next century of immunotherapy will be vastly different from todays current standard of care.

Immunomodulators for allergic respiratory disorders.

New knowledge about the pathogenesis of allergic and immunologic diseases has led to a variety of novel targeted therapeutic approaches. Many immunomodulators are currently under development for the therapy of asthma and allergic and immunologic diseases and are undergoing human clinical trials. The study of immunomodulators in human subjects is ultimately required to determine their therapeutic utility because several agents showing promise in in vitro and animal models have failed in human studies. Novel therapeutic approaches include Toll-like receptor 4 and 9 agonists, immunostimulatory oligodeoxynucleotides, oral and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor gamma, and nuclear factor kappaB are also being evaluated for the treatment of allergic diseases, especially asthma. The anti-IgE mAb omalizumab is already used for the treatment of allergic asthma, but its potential role for other allergic diseases has yet to be clearly defined. Overall, the development of new agents that inhibit specific immunopathogenic mechanisms holds promise for beneficial outcomes for patients with the least amount of risk. However, agents that are too specific in their targets might not exhibit therapeutic benefits because of the redundancy of the immune system and the heterogeneity of diseases such as asthma. The goal of this review is to summarize the data from human clinical trials with immunomodulators, discussing the rationale for their use, efficacy results, and putative adverse events associated with them.

Rationale for new treatments aimed at IgE immunomodulation

OBJECTIVE To review potential or current therapies that decrease IgE synthesis or effects. DATA SOURCES Relevant literature in peer-reviewed journals and abstracts from national meetings. STUDY SELECTION Key articles were selected by the authors. RESULTS Modulation of IgE-mediated diseases can occur at several levels. Transcription factors may be altered to differentiate lymphocytes into a TH1 phenotype, thus decreasing TH2-driven IgE production. This may be accomplished by inhibiting GATA-3 with peroxisome proliferator-activated receptor agonists or promoting T-bet expression with CpG motifs. Inhibiting IgE-promoting cytokines may be accomplished by blocking the effects or synthesis of interleukin 4 (IL-4) or IL-13 by suplatast tosilate. Cytokine therapy with anti-IL-4 or anti-IL-13 has the potential to directly influence IgE-mediated diseases, but strategies aimed at IL-4 alone have been disappointing. Clinical trials with interferon-gamma or IL-12, 2 cytokines important in promoting TH1 and inhibiting TH2 responses, have been fraught with adverse effects that make their use limited. The use of plasmids encoding interferon-gamma or IL-12 has shown promise in animal models. Inhibition of IgE synthesis has been demonstrated with anti-CD23 antibodies. Early human studies have been very encouraging, and larger studies are under way. The only IgE immunomodulator currently available for use is omalizumab. Omalizumab is effective for allergic asthma in children and adults. CONCLUSIONS Newer therapies hold great promise for the future treatment of allergic respiratory diseases, but clinical trials are necessary to accurately evaluate risk-benefit ratios of IgE immunomodulators.

Characterization of asthma endotypes: implications for therapy

OBJECTIVE To describe the concept of precision medicine in treating severe asthma and the utility of relevant biomarkers. DATA SOURCES PubMed was searched for published articles on human clinical trials using biologics for T-helper type 2 cell (TH2)-low and TH2-high asthma. STUDY SELECTIONS Studies were selected if they were double-masked, randomized, placebo-controlled trials published in peer-reviewed journals and relevant to the topic. RESULTS Multiple immune response modifiers have been evaluated in TH2-high asthma geared at blocking interleukin (IL)-5, IL-13, immunoglobulin E, prostaglandin D2, and other pathways. Currently, 3 immune response modifiers approved by the Food and Drug Administration are available for treating severe TH2-high asthma (1 anti-immunoglobulin E and 2 anti-IL-5 monoclonal antibodies) and other TH2-high therapies are in various stages of clinical development. Thus far, many of the TH2-high therapies have shown better efficacy when certain biomarkers are elevated, especially blood eosinophils. The TH2-low endotype does not have any readily available point-of-care biomarkers, so TH2-low asthma is often diagnosed based on a lack of TH2-high biomarkers. These patients tend to have greater resistance to steroids and the development of therapies has lagged behind that for TH2-high asthma. CONCLUSION Two major endotypes for asthma have been described, TH2-high, manifested by increased eosinophils in the sputum and airways of patients, and TH2-low, with increased neutrophils or a pauci-granulocytic profile. Using these classifications and specific biomarkers has led to promising new therapeutics, especially for TH2-high asthma.

Cannabis (hemp) positive skin tests and respiratory symptoms

BACKGROUND We have noted several patients who had rhinitis and/or asthma symptoms when exposed to Cannabis plants in the summer months. Cannabis plants are common in the Midwest. OBJECTIVES To examine whether Cannabis might be a clinically important allergen, we determined Cannabis pollination patterns in the Omaha area for 5 years, the prevalence of skin test positivity, and the association with respiratory symptoms. METHODS Airborne Cannabis (and other weed) pollens were collected using a Rotorod air impactor, and pollen counts were done using a standardized protocol. RESULTS Measurable Cannabis pollen count was not recorded until the last 2 weeks of July. Peak pollination typically occurred during mid- to late-August, and comprised up to 36% of the total pollen counts. Cannabis pollen was not observed after mid-September. To determine the prevalence of skin test positivity, we added Cannabis to the multi-test routine skin test battery. Seventy-eight of 127 patients tested (61%) were skin test positive. Thirty of the 78 patients were randomly selected to determine if they had allergic rhinitis and/or asthma symptoms during the Cannabis pollination period. By history, 22 (73%) claimed respiratory symptoms in the July through September period. All 22 of these subjects were also skin test positive to weeds pollinating during the same period as Cannabis (ragweed, pigweed, cocklebur, Russian thistle, marsh elder, or kochia). CONCLUSIONS The strong association between skin test reactivity, respiratory symptoms, and pollination period suggests that Cannabis could be a clinically important aeroallergen for certain patients and should be further studied.

The Use of Anti-IgE Therapy Beyond Allergic Asthma

Omalizumab is a monoclonal anti-IgE antibody that has been used to treat allergic asthma for over a decade. The use of omalizumab to treat other diseases has largely been limited to case reports until the recently reported large multicenter studies that have established omalizumab as an effective treatment option for chronic spontaneous urticaria. The utility of omalizumab to treat nonallergic asthma and allergic rhinitis and the added safety and therapeutic benefits in combination with allergen immunotherapy have been demonstrated in placebo-controlled trials. Data supporting the clinical efficacy of omalizumab in treating atopic dermatitis, physical urticarias, mast cell disorders, food allergy, and various other allergic disorders have shown promise in small clinical trials and case studies. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab in treating various allergic and nonallergic diseases.

Anti-IgE therapy: Clinical utility beyond asthma

Numerous studies have demonstrated the efficacy and safety of the monoclonal anti-IgE antibody omalizumab in treating patients with perennial allergic asthma. The use of omalizumab for other allergic diseases has not undergone the same level of scrutiny as for allergic asthma, but its effectiveness in the treatment of other atopic diseases has been demonstrated by a number of small studies and case reports (Table I and see also the Reference section in this article’s Online Repository at www.jacionline.org). Allergic rhinitis is an obvious target for anti-IgE therapy. The effect of omalizumab was initially evaluated in patients with ragweed-sensitive allergic rhinitis. Patients were randomized to receive one of 3 doses of omalizumab or placebo just before the onset of the ragweed season and every 3 to 4 weeks throughout the pollen season. Subjects treated with 300 mg of omalizumab demonstrated significantly lower nasal symptoms scores, rhinitis quality-of-life scores, and days missed from work or school when compared with those receiving placebo. This study was among the first to demonstrate a significant correlation between the dose of omalizumab, reductions in serum IgE levels, and improvements in clinical parameters. Omalizumab has been safely readministered to patients with ragweed-induced allergic rhinitis a year after discontinuation, indicating a possible role for preseasonal and coseasonal administration. Similar efficacy in rhinitis symptom improvement has been demonstrated for other pollens, including birch and Japanese cedar. Omalizumab was also shown to be effective in the treatment of perennial allergic rhinitis when patients with moderate-to-severe disease were evaluated. However, the magnitude of the effect was small. When patients with both allergic rhinitis and asthma were treated with omalizumab or placebo, more patients in the omalizumab group demonstrated a clinically significant improvement in both asthma and rhinitis quality-of-life indices (57.7% vs 40.6%). This suggests omalizumab is effective in the treatment of upper and lower airway symptoms in the same patients.

Time-dependent effects of inhaled corticosteroids on lung function, bronchial hyperresponsiveness, and airway inflammation in asthma.

BACKGROUND Exhaled nitric oxide (F(ENO)) and exhaled breath condensate (EBC) are noninvasive markers that directly measure airway inflammation and may potentially be useful in assessing asthma control and response to therapy. OBJECTIVE To examine the time-dependent effects of inhaled corticosteroids on F(ENO) and EBC markers concomitantly with lung function and bronchial hyperresponsiveness. METHODS Eleven steroid-naive adults with mild-to-moderate persistent asthma were treated with mometasone furoate dry powder inhaler, 400 microg/d, for 8 weeks, followed by a 4-week washout. Forced expiratory volume in 1 second (FEV1), the concentration of methacholine calculated to cause a 20% decline in FEV1 (PC20), F(ENO), EBC pH, and EBC nitrite measurements before, during, and after treatment were analyzed and compared. RESULTS The mean (SEM) FEV1 increased from 3.01 (0.13) L (82% predicted) to 3.24 (0.18) L (87% predicted) by week 8 (P < .05). The PC20 level increased from 1.28 (0.31) mg/mL to 2.99 (0.51) mg/mL by treatment week 8 (P < .05) and remained relatively stable through washout week 4 (P < .05). The F(ENO) level decreased from 31.1 (4.1) ppb to 20.6 (4.5) ppb by treatment week 1 (P < .01), remained low through treatment week 8 (P < .01), then trended back to the baseline level by washout week 1 (P < .01). The median EBC pH increased from 7.81 (interquartile range, 7.49-8.09) to 8.02 (interquartile range, 7.87-8.12) by treatment week 4, but did not achieve statistical significance. The EBC nitrite level decreased from 17.6 (1.6) microM to 9.3 (0.9) microM by treatment week 8 (P < .01), and remained low throughout washout week 4 (P < .05). There was a negative correlation between F(ENO) and PC20 (Spearman rank correlation coefficient = -0.50, P < .001). CONCLUSION The F(ENO) level responded the earliest to treatment and withdrawal of inhaled corticosteroids, whereas changes in EBC markers were delayed but more sustained.

Allergic rhinitis and asthma: celebrating 100 years of immunotherapy

Since Noon first described allergen immunotherapy a century ago the basic premise of subcutaneous injections (SCIT) of relevant aeroallergens to induce clinical tolerance has remained true [1]. Indeed, allergen immunotherapy did not change dramatically over the first 75 years, but over the past 25 years there have been a number of important advancements leading to newer approaches and novel formulations. Here we review the top 50 articles published in the past 2 years on allergens, environmental control, and immunotherapy for asthma and allergic rhinitis and the use of immunomodulators in allergic disease.