Immune-related adverse events of immune checkpoint inhibitors: a review

Yin, Qinan; Wu, Lei; Han, Lijuan; Xiao, Zheng; Tong, Rongsheng; Lian, Li; Bai, Lan; Bian, Yuan

doi:10.3389/fimmu.2023.1167975

Cited by 76 publications

(27 citation statements)

References 157 publications

(181 reference statements)

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“…Immune checkpoint blockade, a cornerstone of anti-cancer therapy, aims to inhibit T cell inhibitory receptors like PD-1 and CTLA-4 (69). However, this approach can lead to side effects such as T cell functional exhaustion and immune-related adverse events due to T cell overactivation (70)(71)(72). Our findings reveal that Flot2 deficiency enhances T cell responsiveness to low TCR stimulation, resulting in improved effector responses and tumor control in an in vivo tumor model, while mitigating T cell functional exhaustion.…”

Section: Discussionmentioning

confidence: 99%

Flotillin-2 dampens T cell antigen-sensitivity and functionality

Moon,

Zhao,

Uddin

et al. 2024

Preprint

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T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen sensitivity, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+ T cells exhibited increased T helper 1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and LCK upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single cell-RNA sequencing suggested that Flot2-null CD4+ T cells follow a similar route of activation as wild-type CD4+ T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naive CD4+ T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.

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Section: Discussionmentioning

confidence: 99%

Flotillin-2 dampens T cell antigen-sensitivity and functionality

Moon,

Zhao,

Uddin

et al. 2024

Preprint

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“…Neurological Immune-related adverse events (NirAEs) are considered infrequent and classically described in about 1% of patients [ 3 ]. However, they have been reported more frequently in recent years: 1 to 6% in those receiving monotherapy and up to 14% in those receiving ICI combinations [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, they have been reported more frequently in recent years: 1 to 6% in those receiving monotherapy and up to 14% in those receiving ICI combinations [ 4 ]. Despite their low incidence, NirAEs require significant attention, as they can significantly impact the quality of life and may even be fatal [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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Immune-Related Peripheral Neuropathy Associated with Immune Checkpoint Inhibitors: Case Report and Review of Literature

Bonilla,

Ávila

2024

Case Reports in Oncological Medicine

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Immune checkpoint inhibitors (ICIs) are a group of drugs that have improved outcomes for patients with various cancers. Generally considered safe and well tolerated, these drugs are occasionally linked to immune-mediated or immune-related adverse events. Among these, autoimmune neurological events are rare, displaying varying incidence rates across different studies. Peripheral neuropathy, although one of the more common neurological immune-related events, is at times underestimated. This case report highlights an adult patient diagnosed with metastatic intrahepatic cholangiocarcinoma. Initially, the patient underwent chemoimmunotherapy with gemcitabine, cisplatin, and durvalumab for eight cycles, achieving partial response without significant toxicity. Following this, the patient continued with maintenance monotherapy with durvalumab every 28 days. After completing six cycles of maintenance therapy, the patient suddenly experienced paresthesia and hypoesthesia in four limbs, accompanied by apraxia in the hands that was more pronounced on the right side. Additionally, the patient reported neuropathic pain in the right arm and encountered limitations in certain instrumental activities of daily living. Diagnostic studies, including laboratory and electrophysiological studies, combined with the clinical presentation, identified immune-related peripheral polyneuropathy. Durvalumab was suspended and prednisolone therapy was initiated, resulting in a rapid resolution of all neuropathic symptoms. In addition to the clinical case, this article reviews the literature on immunotherapy-associated peripheral neuropathy.

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“…The activation of the immune system by checkpoint inhibition can lead to undesired off-target effects manifested as autoinflammatory conditions that can occur in any organ. With increasing knowledge of these potentially life-threatening side effects, clinical treatment guidelines for the common irAEs have been established [2][3][4]. Generally, treatment for irAEs is based on corticosteroids, while higher grades of irAE require additional immunosuppressants, and can lead to withholding or cessation of ICI treatment [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Cytokine release syndrome after treatment with immune checkpoint inhibitors: an observational cohort study of 2672 patients from Karolinska University Hospital in Sweden

Hamida,

Karlsson,

Lundqvist

et al. 2024

Preprint

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Immune checkpoint inhibitors (ICIs) are linked to diverse immune-related adverse events (irAEs). Rare irAEs surface first in clinical practice. Here, we systematically studied the rare irAE, cytokine-release syndrome (CRS), in a cohort of 2672 patients treated with ICIs at Karolinska University Hospital in Stockholm, Sweden. We find that the risk of ICI-induced CRS, defined as fever, negative microbiological findings and absence of other probable causes within 30 days after ICI treatment, is approximately 1%, higher than previously reported. ICI-induced CRS was often mild and ICI rechallenge was generally safe. Two out of 28 patients experienced high-grade CRS, and one was fatal. While C-reactive protein and procalcitonin were not discriminative of fatal CRS, our data suggest that the quick Sequential Organ Failure Assessment (qSOFA) score might identify high-risk patients. These data provide a framework for CRS risk assessment and motivate multicenter studies to improve early CRS diagnosis.

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Immune-related adverse events of immune checkpoint inhibitors: a review

Cited by 76 publications

References 157 publications

Flotillin-2 dampens T cell antigen-sensitivity and functionality

Flotillin-2 dampens T cell antigen-sensitivity and functionality

Immune-Related Peripheral Neuropathy Associated with Immune Checkpoint Inhibitors: Case Report and Review of Literature

Cytokine release syndrome after treatment with immune checkpoint inhibitors: an observational cohort study of 2672 patients from Karolinska University Hospital in Sweden

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