Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions. Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation. We further 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 to 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 were 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 under-reporting. 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 might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.

The immune system plays a crucial role to prevent local growth and dissemination of cancer. Therapies based on activating the immune system can result in beneficial responses in patients with metastatic disease. Treatment with antibodies targeting the immunological checkpoint axis PD-1 / PD-L1 can result in the induction of anti-tumor T cell activation leading to meaningful long-lasting clinical responses. Still, many patients acquire resistance or develop dose-limiting toxicities to these therapies. Analysis of tumors from patients who progress on anti-PD-1 treatment reveal defective interferon-signaling and antigen presentation, resulting in immune escape from T cell-mediated attack. Natural killer (NK) cells are innate lymphocytes that can kill tumor cells without prior sensitization to antigens and can be activated to kill tumor cells that have an impaired antigen processing and presentation machinery. Thus, NK cells may serve as useful effectors against tumor cells that have become resistant to classical immune checkpoint therapy. Various approaches to activate NK cells are being increasingly explored in clinical trials against cancer. While clinical benefit has been demonstrated in patients with acute myeloid leukemia receiving haploidentical NK cells, responses in patients with solid tumors are so far less encouraging. Several hurdles need to be overcome to provide meaningful clinical responses in patients with solid tumors. Here we review the recent developments to augment NK cell responses against solid tumors with regards to cytokine therapy, adoptive infusion of NK cells, NK cell engagers, and NK cell immune checkpoints.

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 rechallenge with ICIs after mild CRS was generally safe. However, two out of 28 patients experienced high-grade CRS, and one was fatal. While C-reactive protein (CRP) 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.

Cancer patients are considered to have a higher risk of dying and developing severe Coronavirus Disease 2019 (COVID-19). To date, there are few studies including co-morbidities and sociodemographic...

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. Highlights: Cytokine release syndrome following immune checkpoint inhibition is rare and often mild. Risk assessment using quick Sequential Organ Failure Assessment, but not serum CRP, can potentially detect severe cytokine release syndrome and improve treatment decisions. Rechallenge with immune checkpoint inhibitors after mild cytokine release syndrome is generally well tolerated.

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.