A Phase I Trial of Intravenous Interleukin-6 in Patients with Advanced Cancer

Weber, Jeffrey S.; Gunn, Han; Yang, Jie; Parkinson, Dwight; Topalian, S L; Schwartzentruber, Douglas J.; Ettinghausen, Stephen E.; Levitt, Daniel; Rosenberg, Steven A.

doi:10.1097/00002371-199405000-00008

Cited by 54 publications

(19 citation statements)

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“…Magnetic resonance imaging often reveals no abnormalities, although in 1 case, we noted an abnormality in the splenium, consistent with mild encephalopathy with reversible splenial lesion syndrome (MERS), a syndrome associated with infection and reversible neurologic symptoms. 33 Given the emerging understanding of a central role for IL-6 in CRS and the evidence that IL-6 can directly mediate neurotoxicity, 34,35 it is of interest that MERS has also been reported to be associated with elevated IL-6 levels in the cerebrospinal fluid.…”

Section: Clinical Symptomatologymentioning

confidence: 99%

“…First, IL-6 has been reported to mediate substantial neurologic effects and has been implicated in several neurologic conditions spanning Alzheimer's disease, Parkinson's disease, multiple sclerosis, schizophrenia, depression, and MERS. [34][35][36] Second, elevated central nervous system IL-6 levels are likely to occur in CRS due to direct transit of IL-6 via production in the periphery and/or production of IL-6 via trafficking of activated immune cells to the CNS. Indeed, we have observed elevated IL-6 levels in the cerebrospinal fluid associated with neurotoxicity.…”

Section: Tocilizumabmentioning

confidence: 99%

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Current concepts in the diagnosis and management of cytokine release syndrome

Lee

Gardner

Porter

et al. 2014

Blood

2,229

2,449

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As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.

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Section: Clinical Symptomatologymentioning

confidence: 99%

Section: Tocilizumabmentioning

confidence: 99%

Current concepts in the diagnosis and management of cytokine release syndrome

Lee

Gardner

Porter

et al. 2014

Blood

2,229

2,449

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“…Such knowledge may provide insight into the pathogenetic role of IL-6, since the CRP and sPLA2 are present in blood longer than IL-6. [24][25][26] In dengue patients, 13% had an elevated IL-6 level on admission, 32.4% elevated CRP levels, and 92.5% elevated sPLA2 levels. IL-6 levels were highest on admission and subsequently declined.…”

Section: Discussionmentioning

confidence: 99%

“…This study was designed to detect IL-6 and indirect parameters for IL-6 production: CRP and sPLA2 production are induced by IL-6 and last longer in serum than IL-6. [24][25][26] In one study CRP levels were measured in addition to IL-6 levels but their correlation was not assessed. 22 To our knowledge, type II sPLA2 has been measured only in one dengue study, in which elevated levels were present in 90% of these patients.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory mediators in dengue virus infection in children: interleukin-6 and its relation to C-reactive protein and secretory phospholipase A2.

Juffrie

Meer²,

Hack³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. To assess the potential role of interleukin-6 (IL-6) in the pathogenesis of dengue virus infection, levels of this cytokine were measured in children with dengue virus infection on admission to the hospital. As presumed surrogate markers of IL-6, C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured. Three groups were studied: 33 apparently healthy children as negative controls, 11 children with bacterial infections as positive controls, and 186 children with serologically documented dengue virus infection. One-hundred and fifteen patients had dengue fever (DF) and 71 had dengue hemorrhagic fever (DHF). Compared with healthy controls, dengue shock syndrome (DSS) patients had significantly higher levels of IL-6 on admission (P Ͻ 0.05), comparable with those in positive controls. Dengue patients with shock had significantly higher levels of IL-6 than normotensive patients (P Ͻ 0.001) and higher levels of IL-6 were associated with a higher incidence of ascites. C-reactive protein concentrations in dengue patients and in healthy children were not different, but lower than in children with bacterial infections (P ϭ 0.008). Secretory phospholipase A2 levels were higher in dengue patients than in apparently healthy children (P Յ 0.05) and similar to those in children with bacterial infection. Dengue shock syndrome patients had significantly higher sPLA2 concentrations than normotensive patients (P ϭ 0.02). These data indicate that IL-6 and sPLA2 may have a pathogenetic role only in the most severe forms of dengue virus infection.

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“…66 The smaller molecule IL-6 is known to cross the BBB and has been shown to cause neurologic defects. 67 Saturation of IL-6 receptors following systemic tocilizumab administration may increase serum IL-6 levels, 68 which could theoretically lead to an increase in CSF IL-6 levels that might worsen neurologic toxicity. Similar to other groups, 35 it is our practice to treat severe neurologic toxicities with systemic corticosteroids rather than tocilizumab as the first-line agent.…”

Section: Management Of Neurologic Toxicitiesmentioning

confidence: 99%

Toxicities of chimeric antigen receptor T cells: recognition and management

Brudno

Kochenderfer

2016

Blood

1,081

956

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Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.

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A Phase I Trial of Intravenous Interleukin-6 in Patients with Advanced Cancer

Cited by 54 publications

References 0 publications

Current concepts in the diagnosis and management of cytokine release syndrome

Current concepts in the diagnosis and management of cytokine release syndrome

Inflammatory mediators in dengue virus infection in children: interleukin-6 and its relation to C-reactive protein and secretory phospholipase A2.

Toxicities of chimeric antigen receptor T cells: recognition and management

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