Since their initial introduction into clinical practice, immune checkpoint inhibitors (ICIs) that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death receptor-1 and its ligand (PD-(L)1), and lymphocyte activation gene-3 (LAG-3) have revolutionized the oncology treatment landscape. ICIs are approved for more than 20 different solid tumor types, several hematologic malignancies, and tumors with high tumor mutational burden and microsatellite instability, regardless of tissue type. Despite the profound benefits achieved with ICIs, many patients will develop off-target toxicities known as immune-related adverse events (irAEs), with 87–96 % of patients experiencing any grade irAE and 18–59 % experiencing a severe grade ≥3 irAE [1]. irAEs can affect nearly any organ system and range in severity from asymptomatic to life-threatening. Prompt recognition and treatment can reduce the risk of death for severe irAEs [2]. The primary treatment for most non-endocrine irAEs includes stopping the ICI and using corticosteroids (CSs) as the first-line immunosuppressive therapy (IST). CSs alone are sufficient to resolve irAEs in many cases, but some patients with severe or refractory irAEs may require additional second-line IST [3]. Targeted inhibitors of cytokine pathways are commonly used as second-line agents for severe or refractory irAEs. In this review we will discuss the data supporting the use of cytokine pathways inhibitors for the treatment and prevention of irAEs.

Cytokines are a broad class of soluble proteins which are involved in cell-to-cell communication. Cytokines are produced by immune cells as well as endothelial cells and other stromal cells, and can exert autocrine, paracrine, or endocrine effects on both immune and non-immune cell populations. Cytokine effects are frequently pleiotropic and may vary depending on the local microenvironment but can often be thought of as having an overall net pro-inflammatory or anti-inflammatory effect. Pro-inflammatory cytokines such as IL-1, IL-6, IL-17, tumor necrosis factor-alpha (TNFα), and interferon-gamma (IFNγ) promote inflammation by inducing vasodilation and increasing vascular permeability, enhancing immune cell recruitment, and leading to the clonal expansion of T cell populations [4]. Conversely, anti-inflammatory cytokines including IL-1 receptor antagonist (IL-1RA) and IL-10 counteract the actions of pro-inflammatory cytokines to dampen immune responses [5]. The interplay between pro- and anti-inflammatory cytokines is a complex network with intricate feedback loops intended to allow a robust response to specific inflammatory stimuli, while also having mechanisms to attenuate inflammation and promote resolution and wound healing. Cytokines can also heavily influence the anti-tumor immune response [6,7].

Several groups have analyzed peripheral blood of patients experiencing irAEs to identify cytokines that may serve as biomarkers or contribute to disease pathogenesis. Lim et found that elevated levels of 11 cytokines (G-CSF, GM-CSF, Fractalkine, FGF-2, IFNα2, IL12p70, IL1a, IL1B, IL1RA, IL2, and IL13) at the start of ICI and early on treatment were predictive of high-grade irAEs in melanoma patients [8]. These cytokines were integrated into the CYTOX predictive toxicity score and confirmed in a validation cohort. However, in a different melanoma cohort, patients with grade 3+ irAEs did not have increased baseline levels of 8 of the CYTOX cytokines that were tested. This group did find increased baseline IL-17 levels in patients with pneumonitis, and increased CD40L and Ang-1 in patients with dermatitis. In a cohort of 221 lung cancer patients, elevated baseline levels of IL-1B and IL-2 were associated with irAEs, as were increased levels of IL-5, IFNa, and IFNγ while on treatment [9]. In a different cohort of 111 patients with a variety of solid tumor types, increased levels of IL-5, IL-13, IL-25, IL-6, IL-17f, and TNFa 1–2 months after starting ICI predicted an increased risk of grade ≥2 irAE development [10]. IL-6 and IL-17f were also significantly increased in patients with irAEs at the time of toxicity. Unfortunately, the variation in cancer types, ICI regimens, sample timing, and types of toxicities have made it challenging to identify consistent patterns across studies, and no biomarkers have yet been implemented in clinical practice.

Several groups have examined cytokine expression in irAE biopsies and peripheral blood at the time of irAE onset, aiming to identify cytokines that could be targeted for a more precise approach to irAE treatment. In a cohort with multiple types of toxicity, the chemokine CXCL9 and cytokines IL-17A and IL-15 were amongst the most differentially expressed in patients with irAEs from the baseline timepoint to irAE onset [11]. In checkpoint colitis, elevated expression of TNF, IL1B, IFNy, IL-6, and IL-17 have all been identified in various studies. [[12], [13], [14]]. However, when picking a cytokine to block it is important to also consider the anti-tumor effects of that cytokine pathway. For example, CXCL9, a chemokine important for T cell recruitment and activation, has also been implicated in ICI-colitis [12]. Unfortunately, CXCL9, like many other cytokines that may play a role in irAE pathogenesis are also likely essential for mediating the ICI anti-tumor response and thus there is significant concern that therapeutic blockade of CXCL9 for treatment of irAEs would also lead to loss of the anti-tumor immune response. Herein lies a great challenge in treating irAEs: targeting inflammatory pathways for which the irAE and anti-tumor response is uncoupled.

While cytokine dysregulation or overexpression is one potential mechanism that may contribute to irAEs, there are also multiple other potential mechanisms that may also be initiating or contributing to irAE development. Other possible causes include activation of cross-reactive T cells, autoantibody production, genetic polymorphisms, and the microbiome. One commonly postulated mechanism is that in addition to activating tumor-specific T cells, ICIs may also activate self-reactive T cells. This could either involve activating self-reactive T cells that were previously tolerant or epitope spreading, where T cells that recognize tumor antigens can cross-react with other normal tissues. Several studies have identified T cells that cross-react between cancer-associated antigens and antigens found on healthy tissues [[15], [16], [17]]. Clinically, this is also evidenced by improved tumor outcomes in patients with melanoma who develop vitiligo, an autoimmune skin depigmentation, suggesting T cells that recognize antigens on both the tumor cells and normal melanocytes [18]. Autoantibodies have been identified in several irAEs, including endocrine irAEs, and irAE-associated myasthenia gravis and celiac disease [[19], [20], [21]]. CTLA-4 and PD-1 are both involved in the activation and proliferation of B-cells [22,23], and increased numbers of CD21 positive B-cells after ICI treatment was associated with a higher incidence of the irAE development [24] in a small retrospective study. In addition, the microbiome's impact on both the efficacy and toxicity [25] [[26], [27], [28], [29], [30]]of ICIs has been an area of intense interest over the past decade. Different compositions of bacteria have been linked to increased dendritic cell and T cell activation and infiltration into the tumor, resulting in both improved response to therapy and potentially increased risk of toxicity. Lastly, dysregulation of the cytokine response may play a critical role in amplifying autoimmune processes initiated by any of these other mechanisms, further perpetuating inflammation and organ damage.

Inhibitors of specific cytokines for the treatment of autoimmune disease has been an area of active research for decades with FDA approvals starting in the 1990s for etanercept, a TNFα inhibitor. As a result, numerous FDA-approved cytokine blockade therapies are already available and have demonstrated significant success in the treatment of specific autoimmune diseases [31]. While there are likely subtle differences in the pathogenesis of many irAEs compared to their related non-ICI autoimmune counterpart (e.g., ICI-related enterocolitis compared with inflammatory bowel disease), the basic pathophysiology is thought to share some similarities. Clinically, the choice of second-line IST has been heavily influenced by what is known to be effective in related non-ICI autoimmune conditions. Four major oncology societies (American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) have published guidelines for the treatment of irAEs [[32], [33], [34], [35]]. The recommendations for which cytokine inhibitors to use for second-line IST in these guidelines have largely been based on expert opinion along with case reports and retrospective data about various irAE treatments. Although a limited number of phase I/II prospective trials are currently underway, the relative lack of robust, prospective, randomized evidence to guide irAE treatment represents a major unmet need in the treatment of irAEs that continues to become more urgent considering the increasing use of ICIs and therefore the increasing incidence of irAEs. As we continue to learn more about the pathophysiology of irAEs, the application of cytokine-inhibiting therapy for irAE treatment will continue to be refined.

In this paper, we will review the available data supporting the use of cytokine inhibitors for the treatment of irAEs (Table 1). Additionally, we will discuss trials evaluating the use of anti-IL-6R or anti-TNFa inhibitors for prophylaxis of irAE. Beyond their role in irAEs, cytokines are intricately involved in antitumor immunity and response, presenting a significant challenge in the field: identifying immunomodulatory agents that can effectively treat or prevent irAEs without compromising the antitumor effect.

Prolonged 4–6+ week courses of high-dose corticosteroids (CSs) are the primary first-line treatment for the majority of non-endocrine irAEs. CSs are broadly immunosuppressive, acting on multiple different cell types, cytokine pathways, and phases of the immune response to dampen inflammation [36]. During the initial activation of the immune response, toll-like receptors transmit ‘danger signals’ from pathogen-associated molecular patterns (PAMPs), leading to the production of inflammatory cytokines. CSs inhibit the signaling pathways downstream of the toll-like receptors, blunting the inflammatory response. They also directly inhibit the production of pro-inflammatory cytokines including IL-6, TNFa, IL-4, IL-12, IL-17, and upregulate production of anti-inflammatory cytokines and downstream prostaglandins [[37], [38], [39]]. GC can inhibit the maturation of dendritic cells, which are a type of antigen presenting cell, and skew the T cell response towards Th2 and Th17 cells, rather than Th1 cells. CSs inhibit the trafficking of neutrophils, lymphocytes, and other immune cells into inflamed areas by downregulating both the chemokines that attract leukocytes and the adhesion molecules that enable leukocytes to extravasate out of blood vessels. CSs decrease the activation and proliferation of lymphocytes [40], and can robustly induce apoptosis pathways in naïve and activated T and B cells [41]. As a result of their myriad effects on the immune system, CSs have the potential to significantly compromise the long-term effectiveness of ICIs, highlighting the need to develop more targeted immunosuppressive strategies to treat irAEs without compromising the ICI antitumor response [[42], [43], [44], [45]].

Despite being effective treatment for toxicity in most cases, their use may significantly compromise ICI efficacy. Several pre-clinical studies highlight the potential impact of CSs on tumor responses to checkpoint blockade. In mouse models, the utilization of CSs in conjunction with PD-L1 blockade led to diminished anti-tumor activity and decreased circulating CD8+ and CD4+ T cell populations [43,44,46,47]. CSs can also increase PD-L1 expression on tumor cells and subsequently hinder the anti-tumor efficacy of PD-1 blockade [48,49]. Endogenous CSs produced by macrophage-monocyte interactions can alter the tumor microenvironment by upregulating immune checkpoint protein expression and inducing genes that promote T-cell dysfunction and the subsequent exhaustion of tumor-infiltrating lymphocytes [50]. CSs can cause apoptosis of naïve and activated T cells, including tumor-reactive T cells.

Given the potential for CSs to hamper ICI antitumor efficacy, an increasing body of research is focused on assessing the impact of CS timing, duration, and dosing on tumor outcomes, such as median progression-free survival (PFS) and overall survival (mOS). One study reported outcomes of patients with melanoma who had ipilimumab-induced hypophysitis and received either low dose (≤7.5 mg prednisone or equivalent per day) or high-dose steroids (>7.5 mg prednisone/day) in the following 2 months [45]. Patients who received high dose steroids had significantly shorter overall survival (23.3 months, 95 % CI, 16.0–36.2) and time to treatment failure (11.4 months, 95 % CI, 7.1–19.4 months) compared to the low-dose steroid group (mOS and TTF both not reached). Importantly, both groups had better mOS and TTF than patients who did not develop ipilimumab-associated hypophysitis (mOS 9.5 months; 95 % CI, 8.0–12.9), illustrating that the presence of an irAE itself can be associated with better tumor outcomes. Similarly, Shimomura et al. showed patients who developed an irAE within 60 days of ICI start treated with <0.5 mg/kg prednisone had improved overall survival compared to those treated with higher doses steroids or those who did not develop an irAE; interestingly, there were no significant differences more than 60 days after ICI start [51]. Other retrospective studies have also demonstrated that supra-physiological dosing of steroids at time of ICI initiation is associated with worse survival across multiple tumor types [47,48,[52], [53], [54], [55]]. Decreased overall survival has been particularly associated with patients receiving the equivalent of greater than 10 mg prednisone at the time of immunotherapy initiation and with patients receiving CSs for cancer-related symptoms such as pain, dyspnea, or brain metastases [42,56]. In contrast, other studies have demonstrated that patients treated with steroids for irAE management have comparable survival outcomes to those who did not receive steroids [57,58]. These different conclusions may be attributable to differences in tumor type, ICI used, irAE type and severity, total steroid usage, need for steroid-sparing IST, or method of accounting for immortal time bias. Additionally, the improvement in OS or PFS associated with the development of an irAE could mask a decrease in OS or PFS due to the use of CS. On a methodological note, immortal time bias must be accounted for in all retrospective irAE studies and can affect results [59]. Immortal time bias can be seen in observational studies when there is a period when the study outcome cannot occur for one group – the group is immortal during this time. For example, patients must survive long enough to develop a toxicity and/or be treated with steroids in be analyzed in the irAE or steroid groups, whereas patients in the control group could die prior to when they would have otherwise developed an irAE. Two common methods of accounting for immortal time bias are using a landmark analysis or a Cox regression with a time varying covariate. Kfoury et al. elegantly demonstrated that the method of accounting for immortal time bias can significantly alter the results [60]. They found the occurrence of an irAE was associated with increased mOS when analyzed using a Cox regression model with a time-dependent covariate but found no difference in OS when analyzing the same data using a 12-week landmark analysis. This was due to an early separation of the survival curve in the Cox regression analysis; in contrast, patients who die prior to the landmark time are excluded from a landmark analysis, limiting its statistical power. In conclusion, while the evidence is somewhat mixed, overall, it does appear likely that CSs adversely affect tumor outcomes, particularly when given at high doses early in the course of ICIs. Ultimately, it would be ideal to use a more targeted immunomodulatory therapy that can uncouple treating the irAE from the anti-tumor immune response.

Beyond the potential impact of CSs on ICI antitumor efficacy, both short- and long-term complications associated with GC usage can significantly affect patient quality of life and occasionally result in serious GC-specific toxicities. For example, CSs have been demonstrated to result in reversible myopathy and osteonecrosis leading to poor bone health when prescribed for long periods of time. CSs are also associated with several cardiovascular effects, including edema/fluid retention, weight gain, hypertension, and arrhythmias. Given the immunosuppressive action of CSs there is both a short- and long-term risk of developing opportunistic and serious infections requiring prophylactic antibiotics. Additional AEs of steroid usage include hyperglycemia that can be difficult to manage in patients with pre-existing diabetes mellitus, suppression of the hypothalamic-pituitary-adrenal axis potentially resulting in adrenal insufficiency when steroids are stopped, GI effects including gastritis, gastric ulcer formation and GI bleeding, sleep and motor disturbances, and in rare cases acute psychosis with the elderly being at greatest risk. When the potential impact of CSs on ICI antitumor efficacy and the possibility for severe GC-specific side effects are considered, there is a clear imperative to minimize steroid usage when possible. Targeting specific cytokines represents a promising steroid-sparing approach under investigation for both the prevention and treatment of refractory irAEs. Increasingly, there is growing interest in the earlier use of anti-cytokine antibodies, even in patients who are not refractory, with the goal of facilitating more rapid corticosteroid tapering and reducing cumulative steroid exposure. The approach aims to minimize the overall immunosuppressive effects of prolonged CS use.

Tumor Necrosis Factor alpha (TNFα) is a pro-inflammatory cytokine involved in the pathogenesis of multiple autoimmune diseases [61]. Clinically, TNFα inhibitors are FDA-approved to treat several autoimmune conditions including ulcerative colitis, Crohn's disease, and rheumatoid arthritis. TNFα is produced by macrophages, T cells and natural killer cells [62]. It promotes inflammation by upregulating the expression of leukocyte adhesion molecules and increasing production of other pro-inflammatory cytokines such as IL-6 and IL-8 [63]. TNFα can have both pro-tumor and anti-tumor effects, depending on the context and dose. At physiologic levels, it can induce tumor angiogenesis and promote tumor cell survival and proliferation. At higher concentrations, it has also been shown to cause clotting within the tumor vasculature, leading to hemorrhagic tumor necrosis.

TNFα inhibitors are the most used second-line immunosuppressive agent for irAEs. They are recommended as second-line IST in the irAE treatment guidelines for the treatment of multiple severe or refractory irAEs. They have particularly utilized in treatment of ICI-colitis, leveraging the efficacy of TNFα inhibitors in non-ICI related inflammatory bowel disease. Patients with ICI colitis have been found to have elevated levels of TNFα in the gut mucosa, and upregulated TNFα induced signatures in myeloid cells [12,64,65]. TNFα inhibitors lead to resolution of ICI-colitis in >70 % of patients. Early introduction of TNFα inhibitors has been associated with faster symptom resolution and shorter steroid durations compared to GC alone [66,67]. Additionally, TNFα inhibitors can help prevent colitis recurrence after rechallenging with ICIs [68]. A multicenter retrospective study examined outcomes in patients who required secondary IST with infliximab or vedolizumab (an α4β7 integrin inhibitor which blocks T cell trafficking into the gut) for ICI-colitis resolution [69]. Patients were subsequently rechallenged with ICI either while continuing infliximab (n = 33) or vedolizumab (n = 44) (concurrent group) or without ongoing secondary IST (control group, n = 61). They found 16.9 % of the concurrent group developed grade >3 diarrhea, compared to 34.4 % of the control group (p = 0.028), suggesting that concurrent secondary IST can prevent ICI-colitis recurrence.

Given that TNFα has pleotropic effects and has been associated with both pro-tumor and anti-tumor roles, it is critical to determine if using TNFα inhibitors to treat irAEs will affect the anti-tumor efficacy of ICIs. A promising pre-clinical study by Perez-Ruiz et al. [65] demonstrated that prophylactic TNFα blockade prevents ICI colitis while preserving or even enhancing the anti-tumor response in several different mouse models, suggesting that TNFα inhibitors can be used to treat irAEs without affecting anti-tumor efficacy. However, a large retrospective study used the Dutch Melanoma Treatment Registry (DMTR) to assess the impact of irAE treatments on overall survival in a cohort of 1250 patients [70] suggested a potential association with worse outcomes. In this study, the 312 patients who developed grade ≥3 irAEs had improved OS compared to those who did not develop severe toxicities (23 months vs. 15 months, respectively; adjusted HR = 0.77; 95 % CI.) Patients who required TNFα inhibitors for steroid-refractory toxicities had significantly reduced overall survival compared to patients with irAEs treated with steroids alone (17 months vs. 27 months respectively; adjusted HR = 1.61; 95 % CI, 1.30–2.51.) Notably, the study was limited by several potential confounding factors including missing covariate data and a lack of information about the steroid dose [71]. Additionally, without granular data about the timing of the irAEs the study was not able to fully account for immortal time bias. This study also included a mixed population of melanoma patients, including some who were treated with single agent rather than dual agent ICIs. The authors published a follow-up containing a more homogenous population of patients who all had advanced melanoma treated with first-line ipilimumab and nivolumab. After adjusting for potential confounding variables, patients treated with steroids + second-line immunosuppression had a significantly higher risk of death (adjusted HR 1.54, [95 % CI, 1.03–2.30] compared to patients treated with steroids alone. Patients treated with steroids + TNFα inhibitors had decreased mPFS and mOS in a univariate analysis, but these trends were not significant in a multivariate analysis. Another study with a partially overlapping patient population also demonstrated reduced PFS and OS in patients who received second-line immunosuppression, but an exploratory analysis of 102 patients treated with TNFα inhibitors did not show an effect of the TNFα inhibitor on PFS or OS [72]. Importantly, this study also demonstrated that a higher peak GC dose was associated with worse PFS and OS, but the cumulative GC dose was not. In a systematic literature review and meta-analysis, use of TNFα inhibitors for treatment of irAEs in melanoma patients was associated with worse PFS and OS compared to patients treated with GC alone [73]. Although these retrospective reports raise concerns about the impact of TNF-alpha inhibitors and other secondary IST on tumor outcomes, it is crucial to consider the numerous potential confounding factors inherent in retrospective research.

Currently, irAE treatment guidelines recommend adding TNF alpha inhibitors or other secondary IST agents only for severe or refractory toxicities. Therefore, patients who received secondary IST may be more likely to have also received higher GC doses and may have a higher risk of death from inherently more severe or refractory toxicity. Ultimately, prospective clinical trials will be needed to definitively determine whether adding secondary IST effects tumor outcomes. Promising overall response rates were seen in an open-label phase Ib trial where melanoma patients were treated with ipilimumab and nivolumab combined with an upfront TNFα inhibitor (certolizumab or infliximab) [74]. In the certolizumab arm, 3/6 evaluable patients achieved a complete response (CR) and 3/6 had a partial response (PR), and in the infliximab arm, 1/6 patients had a CR, 2/6 had a PR, and 3/6 had PD as their best response. Clinical trials are also currently underway evaluating whether earlier use of TNFα inhibitors can enhance irAE resolution with lower cumulative steroid exposure (Table 2). Further data from these trials may help elucidate if TNFα inhibitors may have a role in a wider patient population or earlier in the irAE course to help quickly treat irAEs while minimizing steroid side effects.

IL-6 is a pleotropic pro-inflammatory cytokine with multiple roles in the immune response, autoimmunity, and tumorigenesis [75,76]. It is induced by IL-1 and TNFa under inflammatory conditions and induces synthesis of acute phase reactants. IL-6 supports antibody production by inducing B cells to differentiate into antibody-secreting plasma cell and supporting T follicular helper (TFH) cell differentiation. In combination with TGFb and other cytokines, IL-6 drives proinflammatory Th17 cell differentiation and inhibits regulatory T cell (Treg) differentiation. IL-6 and Th17 cells are important mediators of multiple autoimmune conditions [76], and the IL-6R antagonist tocilizumab is FDA-approved for rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, and CAR-T cell cytokine release syndrome. IL-6 is also a pro-tumorigenic cytokine, and has been associated with tumor growth, metastasis, and angiogenesis [75]. As a result of its role both in autoimmunity and promoting tumor growth, there is significant interest in using IL-6 pathway inhibitors for the treatment of irAEs.

IL-6 has been identified as one of the most significantly upregulated genes in biopsies from patients with ICI-colitis compared to matched normal colon biopsies [13]. This finding highlights IL-6 as a potential therapeutic target for the treatment of ICI-colitis. Several groups have also shown a corresponding increase in Th17 cells in ICI-colitis biopsies [77]. Promisingly, when biopsies from melanoma patients responding to ipilimumab were compared to non-responders, IL-6 levels were significantly higher in the non-responding tumors compared to responding tumors [13]. Hailemicheal et al. went on to show in mouse models that IL-6 blockade in combination with anti-CTLA-4 or anti-PD-1 can enhance ICI-induced antitumor efficacy without exacerbating autoimmunity. This study nicely demonstrated the potential for IL-6 inhibition to decouple irAE pathogenesis from ICI antitumor efficacy.

In addition to strong biological rationale that IL-6 can treat irAE without limiting ICI antitumor efficacy generated by preclinical and translational data, numerous studies have demonstrated the efficacy of IL-6R antagonists for refractory irAEs. One retrospective study of 92 patients who were treated with anti-IL-6R antibodies for irAEs found that 73 % of patients had improvement of their irAE to ≤ grade 1, and the tumor overall response rates were similar before and after IL-6R inhibition [78]. Another retrospective, multi-institutional study evaluated clinical outcomes of 22 patients receiving ICIs who received tocilizumab either for irAE treatment (n = 20) or irAE prophylaxis (n = 2) [79]. The median time to irAE resolution was 6.5 days with an overall clinical benefit rate being achieved in 21/22 (95 %) patients. A third retrospective study demonstrated clinical improvement with tocilizumab in 27/34 patients with steroid refractory IrAEs [80]; the majority of these patients were being treated for pneumonitis (12/34), systemic inflammatory response (12/34), or cerebritis (5/34). In the open-label prospective COLAR study, IL-6R blockade with tocilizumab was assessed as a steroid-sparing treatment for ICI-related colitis and arthritis [81]. Twenty patients with steroid-refractory or steroid-dependent grade >1 colitis (n = 9), arthritis (n = 9), or both (n = 2) received tocilizumab 8 mg/kg weekly after a 14-day steroid washout period. Fifteen out of 19 (79 %) evaluable patients experienced clinical benefit, defined as a decrease in the CTCAE toxicity grade within 8 weeks, with a median time to improvement of 14 days. This study demonstrated tocilizumab to be a viable, steroid-sparing option for the treatment of immune-related arthritis and colitis.

A recent prospective clinical trial (NCT03999749) evaluated the potential of giving tocilizumab prophylactically in combination with ipilimumab and nivolumab as upfront treatment for patients with metastatic melanoma. In this single-arm phase II study patients received induction with ipilimumab 1 mg/kg, nivolumab 3 mg/kg, and tocilizumab 4 mg/kg. Ipilimumab was stopped after 4 doses, tocilizumab was stopped after 24 weeks, and nivolumab was continued for up to 2 years. Preliminary results of the study demonstrated a 57 % best overall response rate (BORR) [82], compared to a 47 % BORR in the Checkmate-511 historical control for the same dosing of ipilimumab and nivolumab. The grade 3 and 4 adverse event rate was 22 %, which is lower than the 34 % grade 3-4 adverse event rate seen in Checkmate-511 [83]. Similarly, in another multi-center, phase II study the addition of tocilizumab to high-dose combination ipilimumab 3 mg/kg and nivolumab 1 mg/kg for the treatment of metastatic melanoma demonstrated a reduced incidence of severe irAEs with no detriment to the treatment response rate [84]. In the group treated with standard dosing of tocilizumab 162 mg subcutaneously every 2 weeks, correlative analysis showed that patients who developed grade 3–4 irAEs tended to have higher expression of IL1-7 pathway genes, suggesting the IL-6/Th17 pathway was not completely inhibited. Therefore, they enrolled a dose-dense cohort where tocilizumab was given at 162 mg SC weekly for 6 weeks, followed by every other week for 6 additional weeks, with a slight decrease in grade 3–4 irAEs and slight increase in tumor overall response rate. Combined, these studies suggest that upfront tocilizumab is a promising strategy to reduce irAEs while preserving anti-tumor efficacy.

IL-17 is a pro-inflammatory cytokine that is predominantly produced by Th17 T cells, although it can also be secreted by other immune cells. It plays an important defensive role in barrier organs such as the gut and skin, protects against fungal and bacterial infections, and is involved in wound healing. Increased IL-17 levels can lead to autoimmunity, and IL-17 pathway inhibitors are used clinically to treat psoriasis, ankylosing spondylitis, rheumatoid arthritis, and others [85]. There is evidence that IL-17 can have both pro-tumor and anti-tumor roles, depending on the tumor microenvironment and other cytokines expressed [85,86]. IL-17 is thought to promote tumor growth in the early stages of carcinogenesis. On the other hand, it can also contribute to the activation of IFNγ producing anti-tumor cytotoxic T cells in established tumors. In one study high IL-17 levels were correlated with clinical responses in melanoma patients treated with dual-ICIs, but not single-agent ICI [87]. Another study showed T cell IL-17RA expression correlated with worse patient outcomes in patients with a variety of solid tumors treated with anti-PD-1 ICIs [88]. Like many cytokines, the effect of IL-17 on ICI anti-tumor efficacy likely depends on the context and immune microenvironment. Pre-clinical and translational data have suggested that IL-17 inhibitors may be viable targets for treating and preventing irAEs while maintaining the anti-tumor activity of ICIs. In one mouse model, prednisolone, anti-IL-6, anti-TNFa, anti-IL-25, and anti-IL17RA could all successfully prevent irAE development. However, only anti-IL-17RA and anti-IL-25 preserved the efficacy of anti-PD-1 and anti-CTLA-4 in reducing tumor growth [88]. Another study similarly demonstrated that anti-IL-17A reduced thyroid irAEs without limiting ICI anti-tumor efficacy in a mouse model [89].

There is accumulating evidence that IL-17 may be involved in the pathogenesis of certain irAEs. One patient on dual anti-TIM3/anti-PD-1 therapy developed a multi-system irAE including myasthenia gravis, hypophysitis, and diabetes mellitus that was unresponsive to front-line immunosuppressive therapy [90]. Peripheral cytokine analysis performed at the time of toxicity demonstrated a significant elevation in IL-17A when compared to both healthy controls and patients treated with ICI who did not develop neurological or endocrine toxicities. This patient was treated per clinical guidelines with IVIG, high-dose methylprednisone, and multiple cycles of plasmapheresis but ultimately passed away from his toxicity; he did not receive an IL-17 inhibitor. A translational study by Dimitriou et al. [11] used multiplex immunofluorescence microscopy to demonstrate an increase in Th17 cells in biopsies of ICI-colitis and ICI-dermatitis compared to healthy tissue. They showed an increase in IL-17A levels in the blood from baseline to the time of irAE development, as well as an increase in peripheral blood IL-17A producing CD4 T cells in patients with irAEs compared to those without. They report a proof-of-concept case study where 2 patients with low-grade irAEs (1 patient with myocarditis and colitis, 1 patient with lichenoid dermatitis) that were refractory to high dose methylprednisolone and a TNFα inhibitor were successfully treated with the anti-IL-17A agent secukinumab. Secukinumab was administered subcutaneously at 300 mg per week for 4 weeks, followed by 300 mg every 4 weeks. Both patients experienced complete irAE resolution with secukinumab, with a time to resolution of 43 days for the lichenoid skin rash, 20 days for myocarditis, and 40 days for colitis. Secukinumab was also used prophylactically in one patient to successfully restart ipilimumab without a recurrence of myocarditis. Another patient with a cutaneous psoriasiform irAE secondary to anti-PD-1 blockade was successfully treated with anti-IL17A therapy without affecting his tumor response [91]. Two patients with irAE arthritis were also successfully treated with secukinumab without experiencing tumor progression [92].

Although there is currently not as much clinical experience using IL-17A inhibitors compared to TNFa or IL-6 inhibitors for the treatment of irAEs, these studies and others suggest it is worthwhile to continue to explore this pathway. Currently, IL-17 blockade is only suggested in the NCCN guidelines for psoriatic irAEs.

The IL-12 family comprises several pro-inflammatory cytokines including IL-23 that play an integral role in innate and adaptive immune responses [93]. IL-23 is a proinflammatory cytokine that has previously been shown to play an integral role in the development of autoimmune conditions [94]. IL-23 is a potent upstream regulator of IFNγ which previous pre-clinical models have implicated in the pathogenesis of ICI-related colitis [95]. Pre-clinical studies have demonstrated that IL-23 plays an integral role in the development of immune toxicities and may be a viable therapeutic target. Ju et al. discovered that serum from patients experiencing irAEs exhibits disproportionately higher levels of IL-23 relative to other pro-inflammatory cytokines, and in murine models, IL-23 blockade successfully treated colitis without impacting the anti-tumor activity of dual checkpoint blockade [96].

Clinical reports indicate that IL-23 blockade with ustekinumab can be effective in the treatment of cutaneous irAEs and ICI-related enterocolitis. Ustekinumab is a fully humanized, monoclonal antibody that binds with high affinity to the cytokines IL-12 and IL-23 [97]. Gu et al. conducted a retrospective study in which they identified 14 patients receiving ustekinumab for cutaneous irAEs (12 with psoriasiform rash, 1 with maculopapular rash, and 1 with pyoderma gangrenosum). Ten of 14 patients (71 %) had a response to therapy with 4 having a partial cutaneous response and 6 having a complete response [98]. There is also a case report of ustekinumab successfully treating a patient with steroid-refractory colitis. In this case, the patient had no clinical improvement after high dose GC, infliximab, vedolizumab, and fecal microbiota transplant. The patient was started on ustekinumab with rapid improvement in symptoms with significant downtrend in calprotectin levels [99]. A retrospective study of 19 patients with steroid-refractory colitis treated with ustekinumab in combination with infliximab or vedolizumab reported symptom improvement with 13 patients (68 %) having achieved clinical remission after starting ustekinumab [100]. However, in a separate multi-center cohort of 190 patients with TNFα blockade-refractory colitis, 3 patients received ustekinumab, but none responded to therapy [101]. The ASCO, ESMO, and NCCN consensus guidelines recommend consideration of ustekinumab for ICI-related enterocolitis refractory to CSs and vedolizumab [32,35,102,103].

IL-4/IL-13 are cytokines that promote T helper 2 (Th2) cell activation and survival, and when complexed with the soluble IL-4 receptor (IL-4R) lead to multiple downstream effects that are now understood to be integral to the development of an allergic response [104]. Duplimumab is a fully human monoclonal antibody that binds the alpha subunit of IL-4R, subsequently blocking the downstream signaling of both IL-4 and IL-13 [105]. The precise role that IL-4/IL-13 plays in irAE pathogenesis remains to be fully elucidated, but case reports using duplimumab to treat cutaneous irAEs indicate success in treating ICI-related bullous pemphigoid and other cutaneous irAEs [106] [[107], [108], [109]]. Bullous pemphigoid is a potentially life-threatening autoimmune blistering disease that can occur spontaneously or as a cutaneous irAE either during therapy or up to several months after discontinuing therapy. Spontaneous bullous pemphigoid lesions have been associated with increased frequencies of Th2 cells [110].

The largest retrospective study by Kuo et al. reported outcomes of 39 patients with steroid-refractory cutaneous irAEs of which 34 responded to treatment with duplimumab. Of those treated, 15 (44.1 %) had a complete response to therapy, with an additional 19 (55.1 %) having a significant resolution of symptoms [111]. Patients received standard dosing of dupilumab, with a 600 mg loading dose followed by 300 mg administered subcutaneously every two weeks. Patients included in the study had a median of 8 injections. Dupilumab is currently recommended for the management of cutaneous irAEs by all four major consensus guidelines (Table 1).

IL-5 is a cytokine that plays an integral role in the proliferation, recruitment, and trafficking of eosinophils and has been shown to be a key mediator of type II inflammation [112]. Type II inflammation is a pro-inflammatory pathway that is commonly seen in chronic allergic conditions and is characterized by Th2 CD4+ T-cells that secrete IL-4, IL-5 and IL-13 and is associated with high IgE titers and eosinophilia [113]. The emerging role of IL-5 in mediating irAEs is an area of active investigation and there are no published preclinical data that elucidate the role IL-5 may be playing in irAE pathogenesis. However, case reports indicate a clear benefit for anti-IL-5 therapy in patients with eosinophilia-related irAEs. Rubin et al. report a case series of three patients who developed hypereosinophilia accompanied by dyspnea, arthralgia, myalgia, fasciitis, fatigue, abdominal pain, pruritic, chest pain and ‘morphea-like’ lesions. Two patients were treated with mepolizumab, a monoclonal IgG1 kappa-anti-IL-5 antibody, 100 mg administered subcutaneously, and one patient was treated with benralizumab, a monoclonal IgG1 antibody directed against the alpha chain of the IL-5 receptor, 30 mg subcutaneously. All three patients had rapid reductions in peripheral eosinophilia counts and symptoms. IL-5 blockade is not addressed in any published consensus guidelines for irAE management. Currently, three drugs targeting IL-5 have received regulatory approval including mepolizumab, benralizumab and reslizumab which are approved for hyper-eosinophilic syndromes as well as severe asthma. While its utilization is theoretical with very little clinical evidence to support its use, further investigation into its potential to treat irAEs, particularly those associated with type II inflammation, is warranted.