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Abstract

Clinical and immunologic tolerance are hallmarks of successful allergen immunotherapy (AIT). Clinical benefits such as reduced symptoms, pharmacotherapy intake and improvement of quality of life persist following cessation of treatment. Successful AIT is associated with suppression of allergic inflammatory cells such as mast cells, eosinophils and basophils in target organs. Furthermore, AIT down-regulates type 2 innate lymphoid cells and allergen-specific type 2 T-helper (Th2) cells. The immunologic tolerant state following AIT is associated with the induction of distinct phenotypes of regulatory T-cells (T-regs) including interleukin (IL)-10-, IL-35- and transforming growth factor (TGF)-β- producing T-regs and FoxP3⁺ T-regs. B-cell responses, including the induction of IL-10⁺ regulatory B-cells (B-regs) and the production of IgG4-associated blocking antibodies are also induced following successful AIT. These events are associated with the suppression of antigen-specific Th2 responses and delayed immune deviation in favour of Th1 type responses. Insight into the mechanisms of AIT has allowed identification of novel biomarkers with potential to predict the clinical response to AIT and also novel therapeutic strategies for more effective and safer AIT.

Keywords

allergen immunotherapy allergic rhinitis allergy asthma biomarkers blocking antibodies dendritic cells IgA IgG4 regulatory B-cells regulatory T-cells tolerance

Introduction

Allergic rhinitis (AR) and asthma are common diseases with prevalence estimates of up to 30% for AR and 10–20% for asthma [Bauchau and Durham, 2004; Eder et al. 2006; Bernstein, 2010; Sullivan et al. 2011; Martinez and Vercelli, 2013]. Most patients with asthma have AR while up to 40% of patients with AR also have asthma comorbidity [Cruz et al. 2007; Compalati et al. 2010; Braunstahl, 2011]. Moreover, AR is an independent risk factor in the development of asthma [Guerra et al. 2002]. In western countries, allergic disorders such as AR and asthma have a considerable impact on quality of life [Bauchau and Durham, 2004; Eder et al. 2006; Sullivan et al. 2011]. They affect school performance in children and work productivity in adults [Simons, 1996; Cockburn et al. 1999; Sullivan et al. 2011]. Disease burden is mainly caused by responses on exposure to common aeroallergens derived from grass, birch, pet or house dust mite [Bousquet et al. 2001; Bauchau and Durham, 2004].

Allergen avoidance and pharmacotherapy such as antihistamines and local corticosteroids are the first line treatment management for controlling symptoms in AR [Bousquet et al. 2012; Braido et al. 2014; Jutel, 2014; Scadding, 2015; Wheatley and Togias, 2015]. For asthma control, long acting bronchodilators (LABAs) and inhaled corticosteroids (ICSs) are recommended by current guidelines [Reddel et al. 2015a, 2015b]. Although therapies for AR with or without asthma have proven effective in controlling symptoms and reducing inflammation, a small proportion of patients do not respond to pharmacotherapy and in these patients, allergen-specific immunotherapy may be of importance.

Allergen immunotherapy (AIT), first reported by Leonard Noon in the early 20th century, is a highly effective treatment in individuals with immunoglobulin (Ig)E-mediated diseases [Bousquet et al. 1998; Durham et al. 1999; Calderon et al. 2007; Shamji et al. 2012]. AIT is associated with the reduction of symptoms [Calderon et al. 2007, 2011; Compalati et al. 2014], a reduction in the use of rescue medications, improvement of quality of life [Malling and Bousquet, 2008; Burks et al. 2013; Canonica et al. 2014; Jutel et al. 2015] and induces clinical and immunological allergen-specific immune tolerance [Bousquet et al. 1998; Durham et al. 1999; Bousquet et al. 2001; Calderon et al. 2007; Bousquet et al. 2008; Shamji et al. 2012]. AIT can be administered either by a subcutaneous (SCIT) or sublingual (SLIT) route. Although adequate head-to-head studies comparing SLIT and SCIT are limited, there is a tendency to think that SCIT might be superior to SLIT [Di Bona et al. 2012; Chelladurai et al. 2013; Dretzke et al. 2013]. SLIT is considered to have a safer profile compared with SCIT, with a lower number of anaphylactic reactions. However, local side effects have been reported following SLIT [Fujimura and Okamoto, 2010]. AIT is most often applied in mono-allergy but can also be used in multi-allergic patients.

According to the AR and its Impact on Asthma (ARIA) guidelines [Brozek et al. 2010; Bousquet et al. 2012], AIT is indicated in moderate-to-severe intermittent AR if patients are unresponsive to pharmacotherapy. However, ARIA guidelines only give a conditional recommendation for AIT (both SLIT and SCIT) in allergic asthma due to moderate and low quality evidence [Brozek et al. 2010; Bousquet et al. 2012], while Global Initiative for Asthma (GINA) guidelines indicate that AIT should be considered after pharmacological treatment and allergen avoidance [Reddel et al. 2015a]. Current guidelines state that in clinical practice, uncontrolled asthma is a contraindication for both SCIT and SLIT [Di Bona et al. 2012; Pitsios et al. 2015].

Effects of allergen immunotherapy on early and late phase responses

Both the early and the late phase allergic responses are suppressed after AIT, starting with the late phase response already 2 weeks after the start of treatment [Francis et al. 2008]. Suppression of the IgE-mediated early cutaneous responses is less pronounced and occurs 8–12 weeks after the first dose [Durham et al. 1999; Francis et al. 2008]. Interestingly, mast cell and basophil degranulation is decreased soon after the first injection of AIT [Iliopoulos et al. 1991; Akdis and Akdis, 2015]. In other studies, skin biopsies following AIT have shown reduced numbers of eosinophilic, neutrophilic and basophilic infiltration after AIT [Varney et al. 1993; Nish et al. 1994]. The suppression of late phase responses have been reported in skin, nose and in the lungs [Warner et al. 1978; Pienkowski et al. 1985; Iliopoulos et al. 1991]. Reduction in nasal responses have also been reported for grass pollen, and cat allergens [Nanda et al. 2004; Puggioni et al. 2005]. Allergic asthmatics demonstrated a reduction in late responses after AIT in mite and birch studies [Warner et al. 1978; Arvidsson et al. 2004].

Mechanisms of allergen immunotherapy

A variety of immune cells, such as T-helper lymphocytes type 2 (Th2), eosinophils, mast cells and basophils [Arvidsson et al. 2004; Novak et al. 2011; Shamji et al. 2011], are responsible for the inflammation observed in allergic diseases. Th2 cells play an essential role by producing cytokines such as interleukin (IL)-4, IL-5 and IL-13 that subsequently are responsible for the induction of effector cells. Furthermore, Th2 cells drive B-cells to produce allergen-specific IgE (sIgE). Cellular and humoral responses associated with AIT are presented in Figure 1.

Figure 1.

Mechanisms of immunological and clinical tolerance in AIT. Natural (low-dose) allergen exposure at mucosal surfaces results in a Th2-driven allergic inflammation with mast-cells, basophils and eosinophilic activity. High-dose allergen administered by SLIT or SCIT immunotherapy results in immune deviation from a Th2 to a Th1-driven response. This is accompanied by an increase in the ratio of Th1 cytokines such as IFN-γ and an induction of Treg cells and inducible Treg cells (iTregs) and an increase in the regulatory cytokines such as IL-10. Furthermore, AIT leads to allergen-specific IgG, in particular IgG4 antibodies with inhibitory activity.

Cellular changes

In allergic individuals, cytokines and mediators such as TSLP, IL-25, IL-33 derived from epithelial cells induce dendritic cells (DCs) to polarize naïve T-cell responses towards a Th2 response [Bellinghausen et al. 2001; Hurst et al. 2002; Soumelis et al. 2002; Ito et al. 2005; Schmitz et al. 2005]. AIT results in an induction of tolerant DCs that skew naïve T-cells towards IL-10-producing regulatory T-cells (Tregs) subsequently leading to a Th1 response [Shamji et al. 2011; Akdis and Akdis, 2015]. Several studies have reported the increase of Th1 cytokines and chemokines such as eotaxin, or tumour necrosis factor (TNF)α, paralleled by an upregulation of Th1 [interferon (IFN)-γ, IL-12] and regulatory cytokines [IL-10, transforming growth factor (TGF)β] [Faith et al. 2003; Jutel et al. 2003] although others report no changes [Wachholz et al. 2002; Francis et al. 2003]. It is still believed that these changes in serum cytokines as well as chemokines are immunological paraphenomena of AIT, often not directly correlated with clinical outcome. Also local cytokines indicate a skew towards a more Th1 response; however only a very limited number of studies are available to support these findings [Kirmaz et al. 2011; Scadding et al. 2015]. Recent data also demonstrate that AIT inhibits the seasonal increase of type 2 innate lymphoid cells [Lao-Araya et al. 2014].

A key mechanism in tolerance induction following AIT is the upregulation of peripheral and local allergen-specific Tregs [Bohle et al. 2007; Radulovic et al. 2008; O’Hehir et al. 2009; Rolland et al. 2010; Scadding et al. 2010; Akdis and Akdis, 2014]. Treg cells can be grouped into two subsets, Foxp3+ Tregs and inducible Tregs (iTregs) that produce regulatory cytokines such as IL-10, TGF-β and IL-35 [Bohle et al. 2007; Shamji et al. 2012, 2013]. Several studies have suggested that there is an overlap between these subsets of Treg cells in immunomodulating properties [Akdis and Akdis, 2015]. The early induction of Tregs during AIT has been associated with delayed immune deviation from Th2-type response to Th1-type response, mainly because of increased IL-10 production. Also, the association of increased numbers of Tregs in the nasal mucosa after immunotherapy with positive clinical outcome, as well as the suppression of seasonal allergic inflammation, support a central role for Treg cells in the induction of allergen-specific tolerance [Radulovic et al. 2008; Scadding et al. 2010]. Recently, epigenetic changes of memory Treg cells during dual house dust mite (HDM) and grass pollen SLIT indicated that methylation of the FOXP3 locus might be involved in the mechanism of allergy tolerance after AIT [Mitra et al. 2012].

During AIT, B-cells show a shift from producing the allergenic IgE to the more ‘protective’ IgG4. Although symptoms decrease from the start of AIT, a transient increase in sIgE is observed in serum. Eventually there is a gradual decrease of sIgE in serum over years of treatment [Van Der Neut Kolfschoten et al. 2007]. Specific IgG4 shows a relatively early and rapid increase and continues to increase during AIT. After discontinuation of treatment, sIgG4 decreases again; however it still remains elevated compared with baseline levels [Shamji et al. 2011, 2012].

Apart from antibody production, B-cells also contribute to immune responses through antigen presentation to T-cells and secretion of cytokines. For the production of antibodies B-cells differentiate to plasma cells which can reside for many years in in the bone marrow; even independent of exposure to antigens they can produce antibodies. The upregulated IL-10 suppresses antigen presentation by antigen presenting cells as well Th2 production of IL-4 which leads to a lower IgE production by plasma cells. At the B-cell level, IL-10 enhances the survival, proliferation, differentiation and isotype switching of human B-cells resulting in IgA and IgG4 production.

DCs are specialized antigen-presenting cells and can initiate and sustain allergic inflammation, or support tolerance induction. A recent AIT study demonstrated a significant decrease in the number of DCs and an upregulation of regulatory DCs (DCreg) after SLIT in grass pollen-allergic patients [Zimmer et al. 2012]. Changes in the DCreg/DC2 balance occur after 4 months of SLIT. Changes in DCs were only identified in those patients with a significant decrease in rhinoconjunctivitis symptoms [Zimmer et al. 2012]. After 1 year of SLIT, low production of IL-12 and an increased IL-10 secretion as well as a decreased capacity to mature was observed in HDM-allergic children [Angelini et al. 2011].

Basophils consist of 1% of leucocytes in peripheral blood and contain cytoplasmic secretory granules that have an important role in systemic allergic responses [Ishizaka et al. 1972; Falcone et al. 2011]. Allergen cross-linking of sIgE on basophils initiates degranulation and subsequent release of histamine, leukotrienes, and other mediators of the allergic inflammatory response [Schroeder et al. 1995; Macglashan, 2010]. It has been shown that after AIT, basophil activation is inhibited by preventing allergen IgE interaction or the interaction with FcγRIIb by competitive allergen-specific IgG antibodies, including IgG4 [Van Neerven et al. 1999; Kepley et al. 2000; Wachholz et al. 2003].

Recently, a reverse staining technique for basophil activation was used in which phycoerythrin-conjugated diamine oxidase (DAO) binding histamine within the cell was reduced after degranulation of basophils [Ebo et al. 2012].

The results obtained with basophil activation during AIT in placebo-controlled studies are conflicting. Some authors describe reduction in basophil activation following AIT possibly due to serological factors [Ceuppens et al. 2009; Aasbjerg et al. 2014; Ozdemira et al. 2014; Schmid et al. 2014]. Van Overtvelt and Gomez failed to demonstrate the effects of AIT on basophil activation following AIT [Van Overtvelt et al. 2011; Gomez et al. 2015].

The suppression of basophil activation after discontinuation of AIT has been demonstrated 12–24 months following discontinuation of treatment [Nopp et al. 2009; Lalek et al. 2010; Gokmen et al. 2012; Shamji et al. 2015; Zidarn et al. 2015].

Humoral changes

The gold standard for allergy diagnosis and starting AIT is a serum-elevated sIgE in the context of symptoms in exposure to the relevant allergen [Cox et al. 2011; Burks et al. 2013; Calderon et al. 2013]. Many pollen AIT studies demonstrated transient increases of sIgE levels followed by blunting of the seasonal increases. So far, no functional relevance or severe allergic reactions have been associated with this transient increase. In AIT studies with a long duration, the levels of sIgE levels were shown to decrease over time [Nouri-Aria et al. 2004; Pilette et al. 2007]. For total IgE response during AIT the results are contradictory. Many studies have reported no change while others have reported an increase or decrease in the levels of IgE.

In the mid-1930s, Cooke reported on the induction of serum inhibitory antibody activity following AIT which later proved to be serum inhibitory activity for IgE [Cooke et al. 1935]. It is assumed that mainly antibodies in the IgA and IgG fraction of the serum cause this effect [Lichtenstein et al. 1968; Platts-Mills et al. 1976]. As a result of AIT, increases in the range of 10–100 fold in the concentrations of IgG1 and particularly of IgG4 are observed [Jutel et al. 2005; Reisinger et al. 2005]. Some studies were even able to demonstrate, a correlation between allergen sIgG4 and clinical outcomes [Gehlhar et al. 1999; Moverare et al. 2002; Nelson et al. 2011; Gomez et al. 2015]. After the initial induction of sIgG4 the levels decrease after discontinuation of treatment, although are still elevated compared with baseline levels. It is thought that IgG4 competes with allergen-binding to the IgE on the Fcϵ receptors of mast cells and basophils, and thus acts as a blocking antibody that prevents the activation and degranulation of effector cells [Van Neerven et al. 1999; Wurtzen et al. 2008]. In addition, some other features of IgG4 suggest that it could have an anti-inflammatory role. IgG4 antibodies are dynamic molecules that exchange Fab (facilitating antigen binding) arms by swapping heavy-light chain pairs between IgG4 molecules with different specificities and immune complex formation; whereas they retain their inhibitory activity by competing with IgE for allergens, thereby inhibiting IgE-allergen complex formation [Rispens et al. 2011]. This process results in the production of bi-specific antibodies with a substantially decreased capacity for cross-linking [Aalberse and Schuurman, 2002]. In addition, serum ‘blocking’ IgG4 antibodies have the capacity to suppress both allergen-triggered basophil histamine release and the binding of IgE-allergen complexes to B-cells.

Also, in nasal secretions, IgG levels in allergic individuals are also elevated [Platts-Mills et al. 1976]. More recently, sIgG4 antibodies with inhibitory activity for IgE-facilitated antigen binding (IgE-FAB) were measured in the nasal fluid of SLIT patients [Saleem et al. 2013; Shamji et al. 2013]. It was demonstrated that sIgG4 levels were increased in AIT and that the inhibitory effect was significantly increased compared with untreated patients. An interesting observation was that the magnitude of the suppression was higher in the local antibodies compared with peripheral antibodies [Saleem et al. 2013; Shamji et al. 2013]. Furthermore, the ratio of IgE/sIgG4 was demonstrated to decrease in several SLIT studies and was correlated with a decrease in late-phase skin reaction [Troise et al. 1995; La Rosa et al. 1999; Lima et al. 2002; Bahceciler et al. 2005]; however, this was not a consistent finding [Rolinck-Werninghaus et al. 2005]. One study with genetically modified allergens showed IgG1 and IgG4 in mucosal fluids after AIT. The increase of IgG4 levels was significantly associated with a reduction in nasal sensitivity [Reisinger et al. 2005].

In allergic individuals, allergen-IgE complexes bind to low-affinity IgE receptor FcϵRII (CD23) on the surface of B-cells (IgE-FAB); subsequently activated B-cells would be able to present the allergen to specific T-cell clones. It has been demonstrated in several studies that serum obtained from subjects receiving birch pollen immunotherapy inhibits IgE-facilitated presentation of allergen by B-cells to an allergen-specific T-cell clone [Van Neerven et al. 1999; Wurtzen et al. 2008]. Furthermore, serum obtained from patients that received grass pollen immunotherapy could inhibit IgE-facilitated allergen presentation to a grass-specific T-cell clone [Wachholz et al. 2003]. Specific IgG4 appears to play a key role in this mechanism [Nouri-Aria et al. 2004; James et al. 2011]. IgE-Fab has been shown to decrease after AIT and is modestly correlated with a clinical response to grass and birch AIT up to 2 years after discontinuation of AIT [Van Neerven et al. 1999; Wachholz et al. 2003; Durham et al. 2012].

Follow up on immunotherapy

Clinical follow up

The efficacy of AIT is evaluated by clinical symptoms and rescue medications scores at the time of natural allergen exposure; however there is no validated and generally accepted method for combining clinical parameters with medication scores. An overview of available methods was presented by Pfaar and colleagues in an European Academy of Allergy and Clinical Immunology (EAACI) task force position paper in 2014 [Pfaar et al. 2014]. All advantages and unmet needs of the different methods are listed. The task force highlights combined symptom and medication scores (CSMS) as primary endpoints for AIT in allergic rhinoconjunctivitis. For assessing the disease from the patients’ perspective, the Visual Analogue Score (VAS) is considered to be a useful, easy and (partially) validated measure, to be included in clinical trials on AIT aimed to provide a quantitative evaluation of disease severity [Pfaar et al. 2014; Hellings et al. 2015].

Biomarkers

Biomarkers are quantitative measurements that predict clinical and immunological effects of AIT in the target organ. Markers can be cellular (e.g. Tregs), humoral (sIgG4, IgE/IgG4), molecular (interleukins) or functional (IgE-FAB and blocking factor). Biomarkers could assist in patient selection, identification of responders, target intervention of those who will benefit and to exclude those who are less likely to respond to AIT. Furthermore, they could be of assistance in clinical trials for the development of treatment modalities. Although an overview and recommendations for the standardization of clinical outcomes used in AIT is available [Pfaar et al. 2014], to date there is no consensus on candidate biomarkers that are predictive of the clinical response to AIT [Food and Drug Administration, 2008]. Table 1 presents an overview of studies with a clinical improvement after AIT presenting data on some biomarkers. At present, raised serum sIgE in the context of a clear history of symptoms on exposure to the relevant allergen is the only generally available biomarker for selection of patients for immunotherapy.

Table 1.

An overview of biomarker responses in AIT studies.

Biomarkers	Allergens	Immunologic response	Number of studies	References
sIgG4	Grass	Increased	18	Didier et al. [2007]; Dahl et al. [2008]; Purohit et al. [2008]; Durham et al. [2010, 2012]; Scadding et al. [2010]; Blaiss et al. [2011]; James et al. [2011]; Nelson et al. [2011]; Klimek et al. [2012]; Shamji et al. [2012b, 2015]; Aasbjerg et al. [2014]; Ozdemira et al. [2014]; Keskin et al. [2006]; Amar et al. [2009]; Cox et al. [2012]; Wahn et al. [2012]
		Decreased	2	Ariano et al. [1999]; Zidarn et al. [2015]
		No change	2	Mosges et al. [2007]; Ott et al. [2009]
	HDM	Increased	8	Bousquet et al. [1999]; Lue et al. [2006]; Pham-Thi et al. [2007]; O’Hehir et al. [2009]; Zielen et al. [2010]; Keles et al. [2011]; Yukselen et al. [2012]; Gomez et al. [2015]
		No change	3	Cosmi et al. [2006]; Yukselen et al. [2012]; Wang et al. [2013]
IgE-BF	Grass	Increased	8	Dahl et al. [2008]; Durham et al. [2010]; Blaiss et al. [2011]; Nelson et al. [2011]; Durham et al. [2012]; Shamji et al. [2012b]; Aasbjerg et al. [2014]; Schmid et al. [2014]
	HDM	Increased	1	Corzo et al. [2014]
IgE-FAB	Grass	Increased	7	Scadding et al. [2010]; James et al. [2011]; Durham et al. [2012]; Shamji et al. [2012b, 2015]; Aasbjerg et al. [2014]; Schmid et al. [2014]
sIgE/tIgE	Grass	Increased	1	Di Lorenzo et al. [2009]
	HDM	Increased	2	Di Lorenzo et al. [2009]; Li et al. [2014]
		No change	1	Eifan et al. [2010]

AIT, allergen immunotherapy; HDM, house dust mite; Ig, immunoglobulin; IgE-BF, IgE blocking factor; IgE-FAB, IgE-facilitated antigen binding to B-cells; sIgE/tIgE, ratio of sIgE over total IgE; sIgG4, allergen specific IgG4.

The recent availability of allergen micro-arrays has refined the process to assist in the identification of patients with irrelevant cross-reacting IgE-antibodies to pan allergens. An example is selecting patients for grass immunotherapy on the basis of having IgE-antibodies to Phleum p 1 and/or Phleum p 5, whereas a positive skin test with Phleum extract in the context of a positive Phleum p 12 is likely to represent irrelevant cross-reactivity with the birch profilin Bet v 2.

As mentioned above, many cellular and humoral changes are observed during and after AIT. For example with the increase in sIgG4, some studies were even able to demonstrate a correlation between allergen sIgG4 and clinical outcomes [Gehlhar et al. 1999; Moverare et al. 2002; Nelson et al. 2011; Gomez et al. 2015]. Although after the initial induction of sIgG4 the levels decrease after discontinuation of treatment, they are still elevated compared with baseline levels.

A promising assay for the follow up of AIT is IgE-FAB, an in vitro biofunctional cellular assay that proved to be highly reproducible. It has a within-assay and between-assay reproducibility of 4% and 12% respectively, and can be utilized to detect IgG-associated serum inhibitory activity during as well as after discontinuation of AIT. The assay is highly complex and therefore limited to specialized laboratories. More recently, an alternative and less complex method, an Enzyme-Linked Immunosorbent Facilitated Antigen Binding (ELIFAB) assay, has become available [Shamji et al. 2013].

Some studies show a modest correlation with clinical response to grass or birch and IgE-FAB [Van Neerven et al. 1999; Wachholz et al. 2003]. One study even demonstrated sustained immunological changes of IgE-FAB for 2 years [Durham et al. 2012]. Furthermore, an inverse correlation has been found between symptom scores, rescue medication scores and IgE-FAB [Shamji et al. 2012; Schmid et al. 2014]. Unfortunately to date there are no data available on the possible relationship between IgE-FAB and responders versus nonresponders to AIT.

Concluding remarks

AR and asthma are common diseases that often coincide, while AR itself is an independent risk factor in the development of asthma. Disease burden has an impact on the quality of life and work productivity. When allergen avoidance and pharmacotherapy are not sufficient for disease control, AIT is advised under available guidelines. AIT is an effective, antigen-specific immune-modifying treatment that induces longterm tolerance. The mechanisms involved in AIT become clearer. Skewing from a Th2 response towards a more Th1 profile appears to play a key role in the mechanisms of AIT. IL-10 producing Tregs promote the development of sIgG4-producing plasma cells and sIgG4 competes with sIgE in allergen binding. A better understanding in the underlying mechanisms will eventually lead to novel treatment modalities as well as biomarkers for the follow up of AIT.

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Applications and mechanisms of immunotherapy in allergic rhinitis and asthma

Abstract

Keywords

Introduction

Effects of allergen immunotherapy on early and late phase responses

Mechanisms of allergen immunotherapy

Cellular changes

Humoral changes

Follow up on immunotherapy

Clinical follow up

Biomarkers

Concluding remarks

Footnotes

Funding

Conflict of interest statement

References