Steroid-sparing strategies for managing immune-related adverse events

Abstract

Although immune checkpoint inhibitors (ICI) have greatly improved outcomes in several cancer types, their use is also associated with immune-related adverse events (irAEs) that can impact any organ system and lead to significant morbidity and even mortality. Current approaches to treatment of irAEs largely rely on the use of systemic corticosteroids, which can compromise antitumor immune responses and oncologic outcomes. Prolonged use of systemic corticosteroids is also associated with its own set of toxicities. Thus, there is a critical need for steroid-sparing treatment approaches for irAEs.

In this article, we review the literature for alternative therapeutic approaches for irAEs, which include targeted delivery (alternate routes of administration) of steroids (eg, budesonide) as well as systemic non-steroidal strategies using other mechanisms of action, such as integrin/cytokine blockade, antibody depletion, disease-modifying antirheumatic drugs and fecal microbiota transplant, among others. Many of these approaches have shown significant promise in their ability to induce a clinical response and improve symptoms, even in the setting of steroid-refractory or steroid-dependent irAEs. These approaches are being increasingly used as primary and secondary prophylaxis in patients at high risk of irAEs. Importantly, these strategies may mitigate steroid-associated toxicities, preserve antitumor immune responses and allow continuation of ICI after development of irAEs, hence enabling the full potential of ICI against cancer.

Introduction

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous malignancies with dramatic improvement in outcomes.¹ ICIs modulate the antitumor immune response by blocking inhibitory signals from proteins, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to enhance T-cell activation. However, these inhibitory signals are also involved in tolerance and prevention of autoimmunity, and their blockade can lead to immune-related adverse events (irAEs).^{2 3} The expansion of ICI indications to more cancer types and earlier lines of therapy has contributed to increasing incidence of irAEs. With anti-PD-(L)1 monotherapy, the incidence of any grade irAEs is around 40% and of grade 3 or higher irAEs is around 20%.⁴ The incidence of severe irAEs is higher (up to 50–60%) in patients receiving combination ICI regimens, such as ipilimumab plus nivolumab.⁴ A small proportion of these irAEs can also be associated with significant mortality (eg, 20% mortality for myocarditis), although the overall mortality rate from irAEs is quite low at <1%.⁵

IrAEs could affect any organ system and lead to significant morbidity. Dermatologic, hepatic, gastrointestinal, and endocrine systems are the most commonly affected organ systems. Management guidelines for the treatment of most irAEs include best supportive care, withholding or discontinuing ICI and using immunosuppressive treatment, most commonly with corticosteroids.⁶ Endocrine irAEs, such as type 1 diabetes mellitus and pituitary/thyroid/adrenal dysfunction, represent an exception in that the use of immunosuppression does not generally reverse the acute inflammatory tissue damage that led to the endocrinopathy.7,9 Treatment is instead focused on restoration of the lost endocrine functions using synthetic hormone replacement.^{6 10} Corticosteroids work well in managing most irAEs, and a retrospective review of patients with lung cancer with ICI-related irAEs showed that only 2% of patients required additional immunosuppression on top of corticosteroids.¹¹ However, for severe irAEs, higher doses of corticosteroids (1–2 mg/kg/day of prednisone or equivalent) are often needed, sometimes for prolonged duration spanning several weeks to months.⁶ Unfortunately, prolonged corticosteroid use is associated with a wide array of potential adverse effects. A major concern is the abrogation of the anticancer effects of the ICI,¹² through immunosuppressive mechanisms, such as increased regulatory T cells, decreased number and function of memory CD8+ T cells and effector T cells, and suppression of pro-inflammatory cytokines. These immunosuppressive effects are directly in contrast to the therapeutic intent and mechanism of action of ICI.¹³

Clinical studies have suggested that while the development of any grade irAEs correlates with better cancer outcomes reflecting improved immune activation, the development of more severe irAEs may not necessarily translate into incremental cancer benefit, potentially due to the use of corticosteroids and their immunosuppressive effects and due to higher rates of permanent discontinuation of ICI.¹⁴ Indeed, higher doses and earlier use of corticosteroids after ICI initiation have been associated with worse survival.15,18 The worse outcomes are explained by abrogation of ICI-induced antitumor immune responses and by the use of potentially less efficacious subsequent therapies after irAE development. Overall, there is significant concern regarding the detrimental effects of corticosteroids impacting ICI efficacy and compromising antitumor response, especially with higher doses and more prolonged usage, as compared with a shorter course with an uncomplicated taper. Systemic steroids are also associated with numerous other adverse effects, such as hyperglycemia, adrenal insufficiency, hypertension, fluid retention, weight gain, osteoporosis, myopathy, infections, gastritis, poor wound healing, increased irritability, sleep disturbances, and restlessness.^{19 20}

Due to the above-mentioned detrimental effects of systemic corticosteroids, it is important to explore alternative treatment approaches that may help reduce the overall exposure (including dose and duration) to systemic steroids for irAEs management. Systemic steroid-sparing treatment options may help reduce the morbidity of irAEs, while also preserving the efficacy of ICI treatment and even allowing its continued administration after irAEs. In this review, we discuss several such strategies being used or investigated currently (figure 1). Many of these strategies have been informed by knowledge gained from spontaneous autoimmune diseases, particularly inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), dermatologic disorders (psoriasis), and rheumatic disorders (inflammatory arthritis). Interestingly, application of these strategies to irAEs has also led to better mechanistic insights into the pathogenesis of spontaneous autoimmune diseases. This cross-pollination of ideas raises tremendous opportunities for collaboration between oncology and our subspecialty colleagues to improve care of our patients.

Figure 1. Examples of systemic steroid-sparing strategies for managing immune-related adverse events, their mechanisms of action and emerging applications for their use. CTLA, cytotoxic T-lymphocyte associated protein; DMARDs, disease-modifying antirheumatic drugs; IL, interleukin; irAE, immune-related adverse events; IVIG, intravenous immunoglobulin; JAK2, Janus kinase 2; MMF, mycophenolate mofetil; MTX, methotrexate; R, receptor; TNF, tumor necrosis factor. (NOTE: This figure was created in BioRender).

Targeted delivery of immunosuppressive therapy

One option for decreasing systemic steroid effects is to target treatment delivery toward the site of concern. Ophthalmic, dermatologic, musculoskeletal and gastrointestinal irAEs represent good candidates for “localized” therapy.

Ophthalmic complications

Consensus guidelines developed by a multidisciplinary and international team suggest that many ophthalmic irAE complications can be initially managed with steroid eye drops or intravitreal steroid injections. Management guidelines for immune-related anterior or mild intermediate uveitis include steroid eye drops as frequently as hourly initially with close clinical follow-up every 1–2 weeks until symptoms resolve and consideration of escalation to intravitreal steroid injections. Intravitreal steroid injections are recommended as first-line treatment for immune-related posterior uveitis, panuveitis, Vogt-Koyanagi-Harada-like syndrome, and ocular sarcoidosis. Immune-related dry eye disease is also treated with a variety of local eye-direct therapies including lubricating eye drops, topical tacrolimus, or cyclosporine or steroid eye drops.^{21 22}

Gastrointestinal complications

Most studies investigating the use of a targeted steroid delivery approach for treating gastrointestinal irAEs have focused on the treatment of colitis. Budesonide has been used as a first-line option to treat ICI-induced colitis.^{23 24} Budesonide has extensive first-pass metabolism through the liver and thus relatively little systemic immunosuppressive effects. It is commonly used for the management of milder presentations of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn’s disease. Studies in those populations have demonstrated its efficacy in inducing remission and a better safety profile compared with systemic steroids.^{24 25} A retrospective single-center study of 69 patients with ICI-induced colitis used budesonide as monotherapy in more than half of the patients (56.5%), and as a partner in combination with vedolizumab (21.7%) or with infliximab (10.1%). Budesonide was used as a bridge from systemic steroids for a subset of patients (33.4%) with a median duration of use being 43 days (28–107 days). Outcomes were promising with 75.3% of patients achieving remission and most patients (55.1%) not requiring additional treatment for colitis.^{23 24} Another study showed successful use of budesonide monotherapy in patients with microscopic colitis, while allowing concurrent treatment with ICI.²³

There are also case reports of the successful use of budesonide for the treatment of ICI-induced hepatitis. One case report used budesonide for the treatment of grade 3 ipilimumab-induced hepatotoxicity with near normalization of liver enzymes after 1 month of treatment.²⁶ Two additional case series of two patients each used budesonide to reduce exposure to systemic corticosteroids for the treatment of ICI-induced hepatitis; two patients were able to successfully resume ICI treatment.^{27 28}

Oral irAEs, such as oral mucositis, xerostomia, and lichenoid reactions, are also increasingly being observed in oncology clinics. Mild cases are often managed with best supportive care, such as oral rinses every 2–4 hours; adequate hydration with ≥2 L of water per day; avoidance of tobacco, alcohol, and spicy, acidic, hard, or hot foods; and frequent oral hygiene. Moderate mucositis, xerostomia, and oral lichenoid reactions can be treated with topical corticosteroids, artificial saliva or mucosal coating agents, topical or systemic analgesics, sialagogues, and oral antiseptic agents. However, severe cases generally require systemic corticosteroids.^{29 30}

Dermatologic complications

Topical corticosteroids (such as triamcinolone or clobetasol) are considered first-line therapy for immune-related grade 1–2 maculopapular rash and pruritus.^{31 32} Topical tacrolimus and calcipotriene and narrowband ultraviolet B radiation phototherapy have also been used to treat maculopapular, lichenoid, psoriasiform, and eczematous rashes.^{33 34} However, systemic steroids, generally prolonged courses, are needed for more severe rash,^{31 32} highlighting the need for non-steroidal systemic treatment options for the management of dermatological irAEs.

Systemic non-steroidal approaches

To mitigate the toxicities from prolonged use of systemic steroids, there has been significant interest in the use of systemic non-steroidal treatment options. Currently, many of these agents are used as second-line or beyond treatment after the failure, dependence, or intolerance of first-line corticosteroids.³⁵ A query into the Side Effect Registry Immuno-Oncology (SERIO) identified a total of 1,330 cases of irAEs, of which 16.3% (n=217) received second-line treatment. Tumor necrosis factor-α (TNF-α) antagonists were the most commonly used (46.5%) agents followed by intravenous immunoglobulin (IVIG; 19.1%), mycophenolate mofetil (MMF) (15.9%), and methotrexate (3.6%).³⁵ The use of these therapies led to the resolution of symptoms in 74.3% of cases and an improvement in symptoms in 13.1% of patients,³⁵ highlighting the efficacy of these approaches and raising the question of whether these should also be used in the first-line setting. We highlight below the current landscape of several different approaches for systemic non-steroidal therapies.

Cytokine and integrin blockade

Cytokines and integrins are felt to have a role in the pathogenesis of many irAEs and mediate the inflammation associated with irAEs. Thus, many of the steroid-free approaches focus on preventing pro-inflammatory signaling through cytokine and integrin blockade.^{6 36}

TNF-α inhibitors

TNF-α inhibitors, such as infliximab and adalimumab, have been used for the treatment of irAEs, often as second-line in cases of steroid-refractory irAEs.⁶ These agents have anti-inflammatory effects and are frequently given intravenously or through subcutaneous route to treat IBD, so it was a rational next step to use these agents to treat ICI-induced colitis.³⁷ The SERIO registry showed that 46.5% of patients who needed second-line or additional therapy were treated with TNF-α inhibitors, making it the most commonly used agent for irAEs refractory to the first line of treatment.³⁵

The first studies using infliximab for irAEs were in the setting of steroid-refractory or steroid-dependent colitis. A single-center retrospective study of 75 patients with ICI-induced colitis suggested that adding infliximab to corticosteroids was associated with more rapid symptom resolution (3 vs 9 days, p<0.001), shorter time to steroid taper (4 vs 13 days, p<0.001), possibly lower total days of steroid exposure (median 35 vs 51 days; p=0.15) compared with corticosteroids alone.³⁸ Another case series demonstrated resolution of symptoms without additional use of steroids in 6 out of 7 patients.³⁹

In addition to ICI-induced colitis, infliximab has been successfully used to treat other steroid-refractory irAEs, including pneumonitis^{35 40 41} and hepatitis.⁴² However, it must also be noted that infliximab is not recommended in the American Society of Clinical Oncology guidelines due to reports of infliximab-induced liver toxicity and potential association with decreased survival.^{6 43 44} The SERIO registry showed that infliximab was used not only for the treatment of irAE-related colitis, but also hepatitis, pneumonitis, and arthritis, among others. Infliximab led to resolution of clinical symptoms in 82.6% patients, with 9.6% of patients receiving combination therapy with infliximab plus another agent. An additional 8.7% of patients who received infliximab alone or as part of a combination experienced improvement of symptoms.³⁵

α₄β₇ integrin inhibitors

Vedolizumab, a monoclonal antibody to α₄β₇ integrin commonly used in treatment of IBD, has also been used for the treatment of gastrointestinal irAEs.⁶ Instead of directly suppressing the function of circulating lymphocytes, vedolizumab prevents the trafficking of lymphocytes into the gut by binding the gut-specific leukocyte adhesion protein, α₄β₇-integrin.^{39 45} This specificity of action on the gut without systemic immunosuppression likely preserves ICI-induced antitumor effects and has rendered vedolizumab to be a particularly attractive option for the treatment of ICI-induced colitis and as a prophylactic agent in patients at high risk of the same.

A multicenter retrospective study of 28 patients investigated vedolizumab in patients with steroid-refractory and/or infliximab-refractory colitis. Patients received a median of three infusions of vedolizumab. 24 of 28 patients (86%) were able to achieve and maintain clinical remission. As expected, the remission rates were higher in patients who were infliximab naïve (95%; 18/19) compared with patients who were both steroid and infliximab refractory (67%; 6/9).⁴⁶ Another non-randomized, retrospective study comparing vedolizumab to infliximab suggested that vedolizumab may be associated with fewer days of steroid exposure (35 vs 50 days, p<0.001) but potentially a longer time to clinical response (17.5 vs 13 days, p=0.0012). However, the average time to vedolizumab initiation was also longer than that for infliximab (23 vs 11 days), which may have confounded this result. Clinical remission rates were similar in both arms at 88%.⁴⁵ The SERIO registry also identified three cases of colitis treated with vedolizumab. Vedolizumab was used as second-line therapy, and all three patients experienced complete resolution of symptoms.³⁵ Interestingly, vedolizumab may also be successfully used as prophylaxis against recurrent irAEs. A retrospective study of 77 patients showed that the continued concurrent use of either infliximab or vedolizumab at the time of checkpoint inhibitor re-initiation allowed for successful re-introduction without recurrence of colitis, with a decrease in irAE recurrence rate from 34.4% to 20.8%. However, when looking at each medication separately, 18.2% of patients treated with vedolizumab had irAE recurrence compared with 45% of patients treated with infliximab though there was heterogeneity with regards to checkpoint inhibitor and dose of prophylaxis administered.⁴⁷

Interleukin-6 receptor antagonists

Two interleukin (IL)-6 receptor antagonists, tocilizumab and sarilumab, have been used for the treatment of irAEs. Both are US Food and Drug Administration-approved for the treatment of a variety of autoimmune rheumatologic disorders, including rheumatoid arthritis, polymyalgia rheumatica, polyarticular juvenile arthritis and systemic sclerosis-associated interstitial lung disease, among others. Tocilizumab is often used for the treatment of cytokine release syndrome (CRS) after CAR T-cell therapy. Since IL-6 signaling is associated with a pro-inflammatory response, inhibition of the ligand-receptor interaction can interrupt pro-inflammatory signaling in irAEs.^{48 49}

A systematic review investigated the use of tocilizumab or sarilumab for irAEs. Across all irAEs in a total of 202 patients, the overall response rate was 87.9%. However, the response rates differed by specific irAEs with the highest response rate in CRS (100%) followed by arthritis and polymyalgia rheumatica (88.5%), colitis (80%) and hepatitis/cholangitis (72.9%). Patients with encephalitis (20%) and myositis (0%) did not respond as well.⁵⁰ The TAPIR (Tocilizumab for Arthritis Prevention with Rheumatic irAEs) study retrospectively looked at the use of tocilizumab specifically for irAE-related arthritis. 20 of 26 patients were treated with tocilizumab, and all 20 patients had greater than 70% improvement in symptoms, with 81% of patients not requiring corticosteroids 24 weeks after treatment with tocilizumab. In addition, there were 16 instances of ICI rechallenge. In the 11 cases where tocilizumab was used as prophylaxis, 2 (18%) developed recurrent irAE-related arthritis, but 3 of 5 instances of ICI rechallenge without tocilizumab prophylaxis led to recurrent arthritis.⁵¹ Early results of a phase II clinical trial examining the efficacy of tocilizumab for irAE prophylaxis in combination with ICI suggested that their co-administration could lead to decreased rates of severe irAEs.⁵² The COLAR (Colitis and Arthritis immunomodulation with IL-6 blockade) study was another prospective clinical trial that included patients with ICI-induced corticosteroid-refractory or dependent colitis, diarrhea, or arthritis and showed that 15 of 19 patients (79%) experienced improvement in their symptoms and that 10 of these patients had ongoing complete remission 24 weeks after treatment. 12 patients did not need further treatment with corticosteroids.⁵³

Dupilumab

Dupilumab, a monoclonal antibody binding to IL-4 receptor α (IL-4Rα), is currently used to treat atopic dermatitis, asthma, prurigo nodularis, and eosinophilic esophagitis and is given as a subcutaneous injection. Blockade of IL-4Rα is thought to decrease T helper 2-mediated inflammation and thus dampen the immune response.⁵⁴

Dupilumab is increasingly being used in patients with dermatologic irAEs. A retrospective cohort study of 53 patients treated with dupilumab for steroid-refractory dermatologic irAEs showed that 89% of patients experienced improvement or resolution of their symptoms.⁵⁵ Another retrospective study showed that 34 of 39 patients (87%) with steroid-refractory or steroid-dependent cutaneous irAEs experienced a significant clinical response to dupilumab and that 44.1% (15 of 34) of those responses were complete. Although most patients continued supportive treatment with topical steroids (n=27, 69.3%), few (n=6, 15.4%) needed systemic steroids along with dupilumab. Dupilumab was also well tolerated with only 1 of 39 patients (2.6%) discontinuing therapy due to adverse effects.⁵⁶ There are also case reports of dupilumab being successfully used as the first systemic treatment option after topical steroids for irAE-related dermatitis,^{57 58} treatment for steroid-refractory irAE-related bullous pemphigoid,^{57 59 60} and treatment for a case of irAE-related lichen planus where the patient declined higher doses of corticosteroid use.⁶¹ One single-institution retrospective study on the use of dupilumab for the treatment of bullous pemphigoid identified 16 patients of whom 75% experienced complete resolution of their symptoms. In addition, 10 of these patients who achieved a complete response were treated with single-agent dupilumab without concurrent corticosteroids.⁶⁰

Interleukin-23 inhibitors

Recent studies have also demonstrated the successful use of ustekinumab, an anti-IL-12 and anti-IL-23 antibody that is used to treat IBD, in the setting of refractory ICI-induced colitis^{62 63} and dermatologic irAEs.^{64 65} Case reports (n=3) have suggested the effectiveness of ustekinumab in patients with colitis refractory to steroids, vedolizumab, infliximab, and/or fecal microbiota transplant.^{62 63} Ustekinumab improved clinical symptoms in 73% of patients with cutaneous irAEs (n=11) and decreased the use of topical steroids from 91% to 56%, and systemic steroids from 64% to 36%.⁶⁴ Guselkumab, another anti-IL-23 antibody, was successfully used to treat ICI-induced psoriatic arthritis in a single case report.⁶⁶

Interleukin-17A inhibitors

Secukinumab and ixekizumab are IL-17A inhibitors, while brodamulab is an IL-17A receptor antagonist. All are used to interrupt the pro-inflammatory IL-17 signaling pathway and treat a variety of rheumatologic and dermatologic conditions, such as psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.⁶⁷ The use of IL-17A inhibitors in irAEs has primarily been published as case studies for the treatment of ICI-induced arthropathy⁶⁸ and psoriasis.^{69 70} Interestingly, a recent study showed that increased IL-17A expression on CD4+T cells was associated with the onset of irAEs.³⁶ The research team then validated their theory by treating two patients with corticosteroid-refractory and multiple concurrent irAEs with secukinumab. Both patients experienced improvement or resolution of their symptoms after treatment, and one patient was successfully re-challenged with ICI with no irAE recurrence.

Future directions for integrin and cytokine blockade

Several studies have demonstrated the utility of cytokine blockade in the management of steroid-refractory irAEs. Given their success in inducing complete clinical responses and decreasing systemic steroid use, it may be worthwhile examining the use of these medications in the front-line setting. Most importantly, we need better therapeutic options, such as vedolizumab, whose activity is restricted to the target organ of interest, hence limiting systemic immunosuppression and preserving antitumor immune responses induced by ICI. Overall, anticytokine approaches may decrease or help avoid the use of corticosteroids and their side effects, be used as primary or secondary prophylaxis for irAEs in high-risk situations, and most importantly, may not impair the antitumor effect of ICIs.⁷¹ Indeed, there are several clinical trials investigating the use of cytokine blockade in the first-line setting or as prophylaxis. Examples include studies comparing infliximab to corticosteroids as first-line treatment of ICI-induced colitis (NCT04305145), investigating the efficacy of vedolizumab in combination with corticosteroids in the front-line setting (NCT06841705), and comparing the efficacy of infliximab to vedolizumab (NCT04407247) in decreasing corticosteroid use. The efficacy of ustekinumab plus corticosteroids (NCT06807593) for ICI-induced colitis, as well as the use of brodalumab (NCT06673329) for irAEs thought to be IL-17 mediated is also being studied in a prospective clinical trial. Trials exploring cytokine blockade for irAE prophylaxis include adding infliximab (NCT05034536), dupilumab (NCT06637306, NCT05013450), and tocilizumab (NCT04940299) to ICI for a broad range of cancers. As we identify new mechanisms involved in irAEs in different tissues, we may identify additional cytokine targets to be explored as steroid-sparing approaches.

Antibody depletion

B-cell activation and secretion of autoreactive antibodies is postulated to contribute to the pathogenesis of certain irAEs such as neurologic, rheumatologic, and renal irAEs.72,75 Hence, strategies to remove or deplete autoantibodies have been explored in the management of these irAEs. Rituximab has been used to deplete antibody-producing B-cells, IVIG has been used to neutralize autoantibodies, and plasmapheresis has been used to remove autoantibodies from systemic circulation.

Rituximab

A systematic review identified a total of nine patients with irAEs treated with rituximab that ranged from myasthenia gravis to Sjögren’s and neuropathy. They reported that 6 of the 9 patients experienced improvement in symptoms.⁷⁶ Another case series demonstrated that all five patients who received rituximab to treat irAE-related renal vasculitis had a partial or complete response. Two of these patients also underwent plasmapheresis.⁷⁷ There are also case reports of the effective use of rituximab for the treatment of irAE-related membranous nephropathy in a patient who was successfully rechallenged with ICI⁷⁸ and for a patient with myasthenia gravis who was refractory to steroids, IVIG, and pyridostigmine.⁷⁹

Plasmapheresis or IVIG

Plasmapheresis or IVIG is recommended for ICI-induced myasthenia gravis and Guillain-Barré syndrome in the second-line setting or concurrently with corticosteroids.^{6 80 81} However, there are questions regarding the optimal timing of plasmapheresis and IVIG and whether earlier use, especially in cases of severe irAEs, may improve outcomes.⁸²

A retrospective single institution study investigated the use of plasmapheresis or IVIG as part of first-line therapy compared with patients who were treated with corticosteroids alone. They showed that patients who underwent plasmapheresis or received IVIG as part of first-line treatment were more likely to experience an improvement in symptoms compared with those treated with steroids alone (95% vs 63%, p=0.011). In addition, they demonstrated that plasmapheresis and IVIG did not have the same efficacy when used in the second-line setting after single-agent corticosteroid use.⁸³ This highlights the importance of treatment sequencing and raises the question of whether plasmapheresis and/or IVIG should potentially be used as an earlier line of therapy to both improve treatment efficacy but also to avoid corticosteroid-related adverse effects.

In addition to the treatment of myasthenia gravis, there are also case reports of successful use of plasmapheresis in ICI-induced encephalitis, myocarditis, thrombotic thrombocytopenic purpura, renal vasculitis, and myositis.⁸² IVIG has also been successfully used to treat ICI-induced pneumonitis,⁴⁰ scleroderma-like syndrome,⁸⁴ and toxic epidermal necrolysis.⁸⁵

Future directions for antibody depletion

Currently, the most promising antibody-depletion strategy is plasmapheresis and/or IVIG for the treatment of ICI-induced myasthenia gravis. Early data suggest that there may be benefit from earlier initiation, but prospective clinical trials are needed to confirm these early findings. The impact on steroid dose and duration, as well as antitumor efficacy, also needs to be investigated. However, myasthenia gravis is a relatively rare irAE, and recruitment for prospective specific clinical trials would be challenging. Additionally, although rituximab, plasmapheresis, and IVIG have successes in a wide range of multiply refractory irAEs, it is currently unclear if they would be widely applicable or have similar benefit if moved to earlier lines of therapy.

Disease-modifying antirheumatic drugs

Another category of systemic non-steroidal agents to treat irAEs is disease-modifying antirheumatic drugs (DMARDs), such as MMF, methotrexate, hydroxychloroquine, mechanistic target of rapamycin inhibitors, calcineurin inhibitors, Janus kinase (JAK) inhibitors, and CTLA-4 agonists, among others.⁸¹ MMF and methotrexate are commonly used to mitigate steroid-related side effects from prolonged use. Hydroxychloroquine offers a relatively less immunosuppressive choice, but its efficacy is likely limited to milder cases only. Increasingly, many of the synthetic DMARDs are being used to treat severe or refractory rheumatological irAEs.⁶ However, while they provide a non-steroidal alternative, some agents are also associated with significant immunosuppressive side effects that may also limit their use.⁸⁶

A meta-analysis study described the use of JAK inhibitors including ruxolitinib, tofacitinib, upadacitinib, and baricitinib in 104 patients for the treatment of a wide array of irAEs.⁸⁷ Myocarditis was the most common indication (70%) followed by myositis (33%), hepatitis (24%), and colitis (11%). Nearly all patients (99%) had previously been treated with corticosteroids. 68% of patients experienced resolution of their irAE after treatment, while 13% experienced improvement in symptoms. JAK inhibitors were also well tolerated with 91% of patients experiencing no adverse effects, though 7% of patients experienced an infectious adverse event.

There is also considerable excitement about the combination of ruxolitinib and the CTLA4 fusion protein abatacept for the treatment of ICI-induced myocarditis and the “triple-M” syndrome—the combination of myocarditis, myositis, and myasthenia gravis.⁸⁸ These irAEs are associated with a high mortality rate, so there is an urgent need for safe and effective treatments in this space. Abatacept and ruxolitinib are thought to synergistically work together to inactivate T-cell signaling. One single-institutional study looked at ICI-induced myocarditis outcomes in patients who received standard-of-care corticosteroids followed by second-line therapies versus patients who received abatacept and ruxolitinib in addition to corticosteroids. The results of this study were striking in that 6 of 8 patients with grade ≥3 myocarditis died from myocarditis when treated with corticosteroids alone as first-line therapy, but only 1 in 22 died from myocarditis in the group treated with abatacept and ruxolitinib. Patients who were treated with abatacept and ruxolitinib were also exposed to lower doses of corticosteroids.⁸⁹

Future directions for DMARDs

Earlier incorporation of DMARDs, alone or as a partner with other agents, into irAE management needs to be investigated in prospective clinical trials. The success of the combination of abatacept and ruxolitinib for an irAE with a high mortality rate raises the question of its use in the front-line setting. The ATRIUM (Abatacept in Immune Checkpoint Inhibitor Myocarditis) trial (NCT05335928) is investigating whether the addition of abatacept to standard of care can improve ICI-induced myocarditis outcomes. However, this clinical trial does not incorporate ruxolitinib and also uses relatively lower doses of abatacept. Additional trials looking at the combination of abatacept and ruxolitinib, and/or higher doses of abatacept may be necessary to fully address the question. In addition, long-term outcomes regarding antitumor impact and immunosuppressive effects remain unknown. This is especially true because the mechanism of action of abatacept as a CTLA-4 fusion protein to inhibit T-cell activation is directly contradictory to the mechanism of action of ipilimumab, which is a CTLA-4 inhibitor that removes its break on T-cells. Thus, the European Alliance of Associations for Rheumatology recommends caution when using abatacept in patients with a history of cancer.⁹⁰ However, both abatacept and ruxolitinib remain an exciting systemic non-steroidal therapeutic option that should be further investigated for not only myocarditis but also other severe, life-threatening irAEs.

Fecal microbiota transplants

The ideal treatment approach to manage irAEs is one that targets the immune system in the affected organ, while not interfering with the antitumor effects of the ICI and, hence, allowing continuation of the same for cancer control. Fecal microbiota transplants (FMT), which have been investigated as a treatment for ICI-induced colitis, may represent one such treatment.

Several studies have shown that the gut microbiome can influence the local immune response to ICI therapy and that alterations in the microbiome may predispose to ICI-induced colitis.91,93 FMT has been shown to successfully treat patients with recurrent Clostridium difficile infection⁹⁴ and ulcerative colitis.^{95 96} Thus, it was hypothesized that it may also be successfully used to treat ICI-induced colitis. The first study enrolled two patients with ICI-induced colitis who had persistent symptoms despite treatment with multiple lines of therapy. They were then treated with FMT via delivery of donor stool via colonoscopy. Both patients experienced resolution of diarrhea, abdominal pain, and endoscopic findings of inflammation and ulceration.⁹⁷ Another case series treated 5 patients with steroid-refractory colitis with up to two FMT treatments and reported symptomatic improvement in 4 of 5 patients.⁹⁸

In addition to the benefit of treating irAE-colitis, there are also studies suggesting that FMT can potentiate antitumor responses by restoring gut microbial diversity, leading to improved gut barrier repair and reducing dysbiosis-induced inflammation that can underlie malignancy. Additionally, it can also promote a microenvironment more supportive of CD8+T cells and dendritic cells, which also lead to enhanced antitumor responses.^{99 100} Challenges with this approach include the difficulties associated with colonoscopy as the method of delivery and whether donor source may impact the efficacy of this method.⁹⁵

There are several in-progress clinical trials examining the use of capsules for delivery of FMT (NCT06499896, NCT05726396), the use of FMT as prophylaxis (NCT03819296) and as a front-line option (NCT06206707) for ICI-induced colitis.

Conclusion

There is a growing need to investigate novel steroid-sparing strategies to manage irAEs that can mitigate the significant deleterious effects associated with prolonged use of high-dose systemic corticosteroids. The ideal steroid-sparing agent should target specifically the site of concern to preserve systemic antitumor immune responses. The currently available non-steroidal approaches, including cytokine and integrin blockade, antibody depletion, DMARDs, and FMT, have successfully treated steroid-refractory or steroid-dependent irAEs and are worthy of being explored further in the front-line setting and as prophylaxis in high-risk situations. Prospective investigations of innovative approaches, including multi-institutional collaborations to facilitate timely patient enrollment, should be prioritized to harness the maximum potential of ICIs against cancer.