Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

Abstract

BackgroundManagement of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs.MethodsWe performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment.ResultsWe identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04).ConclusionTargeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299,NCT03999749).

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors

“…Because our results suggested that the IL-6 classical signaling, but not trans-signaling, may be related to the anti-tumor immune responses in NSCLC patients treated with ICIs, anti-IL-6 or anti-IL-6R Abs, but not sgp130 fusion proteins, may be promising to improve the efficacy of ICIs. Indeed, combined ICI and anti-IL-6 or anti-IL-6R Abs have been reported to potentially enhance anti-tumor immunity or reduce immune-related toxicity in preclinical ( Mace et al, 2018 ; Hailemichael et al, 2022 ) and clinical studies ( Fa’ak et al, 2023 ). Therefore, to facilitate personalized immunotherapy, further clinical trials are recommended to validate the effects of anti-IL-6 or anti-IL-6R Abs in ICI-treated NSCLC patients with high plasma IL-6 levels.…”

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

“…In contrast to corticosteroids that generally suppress various inflammatory pathways, cytokine inhibitors offer a more precise clinical method to diminish inflammation caused by ICIs in NSCLC 91 . Cytokine inhibitors, including anti‐TNF‐α agents (infliximab, etanercept, adalimumab) and anti‐IL‐17A agents (secukinumab) inhibitors, as well as cytokine receptor inhibitors, such as IL‐6 (tocilizumab) or IL‐α4β7 receptor (vedolizumab) inhibitors, have been investigated for their efficacy in managing steroid‐resistant irAEs in NSCLC 91,158,178 . Notably, TNFα inhibition has shown effectiveness in treating severe and refractory irAEs, such as colitis, inflammatory arthritis and hepatitis, in NSCLC and other cancer types 179‐181 .…”

“…Notably, TNFα inhibition has shown effectiveness in treating severe and refractory irAEs, such as colitis, inflammatory arthritis and hepatitis, in NSCLC and other cancer types 179‐181 . A recent multicentre study found that inhibition of the IL‐6 receptor improved irAEs in 73% of patients with NSCLC and other cancers without affecting tumour immunity 178 . Additionally, tocilizumab was notably effective in treating nivolumab‐induced pneumonitis, with a 79.4% positive response in patients with NSCLC 158 .…”

Tissue‐resident memory T cells in immunotherapy and immune‐related adverse events by immune checkpoint inhibitor

“…In the recent meta‐analysis, TNF‐α blockade is the most reputable strategy in the management of steroid‐refractory ICIs‐induced enterocolitis 112 . Recently, a retrospective multicenter study assessed the impact of anti‐IL‐6R therapy on irAEs and antitumor immune response 113 . The administration of anti‐IL‐6R antibodies (tocilizumab or sarilumab) resulted in a rapid improvement in irAEs including inflammatory arthritis, hepatitis/cholangitis, encephalitis, polymyalgia rheumatica, diffuse systemic sclerosis, interstitial nephritis.…”