Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Hailemichael, Yared; Johnson, Daniel; Abdel-Wahab, Noha; Foo, Wai Chin; Bentebibel, Salah-Eddine; Daher, May; Haymaker, Cara L.; Wani, Khalida; Saberian, Chantal; Ogata, Dai; Kim, Sang T.; Nurieva, Roza; Lazar, Alexander J.; Abu-Sbeih, Hamzah; Fa’ak, Faisal; Mathew, Antony; Wang, Yinghong; Falohun, Adewunmi; Trinh, Van Anh; Zobniw, Chrystia M.; Spillson, Christine; Burks, Jared K.; Awiwi, Muhammad O.; Elsayes, Khaled M.; Solis, Luisa M.; Melendez, Brenda; Davies, Michael A.; Wargo, Jennifer A.; Curry, Jonathan L.; Yee, Cassian; Lizee, Gregory; Singh, Shalini; Sharma, Padmanee; Allison, James P.; Hwu, Patrick; Ekmekçioglu, Sühendan; Diab, Adi

doi:10.1016/j.ccell.2022.04.004

Cited by 169 publications

(141 citation statements)

References 47 publications

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“…Using mouse models, they showed that IL-6 blockade significantly reduces Th17 cells and increas-esCD4+/CD8+ T cells, macrophages and myeloid cells, enhancing immunotherapy-mediated inhibition of tumor growth. These findings clearly support the combination trials of IL-6 blockade and immunotherapy for enhancing antitumor immunity while inhibiting autoimmunity [7].…”

Section: Translational Studiessupporting

confidence: 69%

Research highlights in cancer immunotherapy from basic discovery to clinical trial

Wang

2022

Holist Integ Oncol

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Cancer research is one of the most active areas in the biomedical sciences. Recently, the tumor immune environment, crosstalk between tumor cells and immune cells, and immunotherapy remain the “hot” topic in the field of cancer research. This short review will highlight the recent interesting findings in cancer research associated with cancer immunology and immunotherapy from basic discovery, translational study to clinical trials.

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Section: Translational Studiessupporting

confidence: 69%

Research highlights in cancer immunotherapy from basic discovery to clinical trial

Wang

2022

Holist Integ Oncol

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“…Key factors in this decision-making process are the risk of recurrence of a given irAE, the anticipated severity in case of recurrence, as well as its treatability. A recent study has suggested that IL-6 blockade given in parallel with ICIs ameliorates irAEs, while enhancing the antitumoral effect of ICIs 66 . Earlier experimental data had already hinted at the potential benefit of adding IL-6 inhibitors to ICIs in mouse models of pancreatic cancer 67 (which is largely resistant to ICI therapy), as well as hepatocellular carcinoma 68 .…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: Systematic review of the literature

Liu

Skribek

Harmenberg

et al. 2022

Preprint

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Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events (irAEs). As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions. Here, we provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase, and the Web of Science Core Collection from inception until October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n = 1866 articles, which were assessed for eligibility independently by two examiners. Of those, n = 49 articles reporting on n = 189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment was reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial underreporting. The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and non-fatal in the majority of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.

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“…Similarly, the use of IL-6R inhibitors in an experimental model of ICI-treated tumour showed a decoupling effect by increasing antitumour response while mitigating toxicity. 21 First data of an ongoing phase II clinical trial assessing the combination of tocilizumab with nivolumab and ipilimumab (NCT03999749) are promising with a reduction of severe irAEs and a similar or possibly increased tumour response compared with patients without tocilizumab. 22 Combination of anti-PD-1 and rituximab has been safely used in patients with relapsed follicular lymphoma but recent insights into the role of B cells in the response to ICI would deserve further data on such combination.…”

Section: Discussionmentioning

confidence: 99%

Use of a bDMARD or tsDMARD for the management of inflammatory arthritis under checkpoint inhibitors: an observational study

et al. 2022

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ObjectiveThere is limited experience regarding the use of biological disease-modifying antirheumatic drug (bDMARD) and JAK inhibitor (JAKi) for the management of immune checkpoint inhibitors (ICI)-induced inflammatory arthritis. We aimed to assess their efficacy and safety in this setting.MethodsUsing the Club Rhumatismes and Inflammation French network, we conducted a multicentre, retrospective, observational study of patients with cancer diagnosed with inflammatory arthritis under ICI(s) and treated with bDMARD or JAKi. Clinical data were collected using a standardised case report form.ResultsTwenty patients (60% men, median age 69.5 years) were included, with rheumatoid arthritis (RA)-like (n=16), polymyalgia rheumatica-like (n=2) or psoriatic arthritis-like (n=2) clinical presentation. Two patients had pre-existing RA. 90% were treated with glucocorticoids as first-line therapy and 60% received methotrexate prior to bDMARD or JAKi. Anti-interleukin-6 receptor (IL-6R) therapy was used in 13/20 patients (65%), leading to clinical improvement in 11/13 patients (85%), but one patient experienced intestinal perforation and cancer progression was noticed in 6/13 patients (46%). Tumour necrosis factor inhibitors were used in 5/20 patients (25%), with improvement in 4/5 patients (80%) and cancer progression was observed in 3/5 patients (60%). Two infections (diverticulitis and pneumonitis) were reported. Anakinra, baricitinib and ustekinumab were each used in one patient. Median duration of the bDMARD or JAKi was 17 weeks.ConclusionAnti-IL-6R therapy is currently the most common strategy in patients with ICI-induced inflammatory arthritis and insufficient response to glucocorticoids and methotrexate, leading to improvement in >80%. Overall, cancer progression occurred in about half of patients and whether the bDMARD/JAKi impacted the tumour response remains to be determined.

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Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Cited by 169 publications

References 47 publications

Research highlights in cancer immunotherapy from basic discovery to clinical trial

Research highlights in cancer immunotherapy from basic discovery to clinical trial

Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: Systematic review of the literature

Use of a bDMARD or tsDMARD for the management of inflammatory arthritis under checkpoint inhibitors: an observational study

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