FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome

Le, Robert Q.; Li, Liang; Yuan, Weishi; Shord, Stacy S.; Nie, Lei; Habtemariam, Bahru; Przepiorka, Donna; Farrell, Ann T.; Pazdur, Richard

doi:10.1634/theoncologist.2018-0028

Cited by 683 publications

(610 citation statements)

References 20 publications

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“…Tocilizumab is an IL‐6 receptor antagonist that has been shown to lead to rapid resolution of CAR‐T–induced CRS and is FDA‐approved for the treatment of severe CRS based on a retrospective analysis of 45 patients (median age, 12 years) who were treated with CD19 CAR‐T cells and received tocilizumab for CRS; the response rate was 69% …”

Section: Adoptive Cellular Therapymentioning

confidence: 99%

A review of cancer immunotherapy toxicity

Kennedy

Salama

2020

CA A Cancer J Clinicians

839

699

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Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune‐modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

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Section: Adoptive Cellular Therapymentioning

confidence: 99%

A review of cancer immunotherapy toxicity

Kennedy

Salama

2020

CA A Cancer J Clinicians

839

699

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“…3 CAR-T treatment is frequently complicated by cytokine release syndrome (CRS), 4,5 which manifests with fever, hypotension, and vascular leak. 3 CAR-T treatment is frequently complicated by cytokine release syndrome (CRS), 4,5 which manifests with fever, hypotension, and vascular leak.…”

mentioning

confidence: 99%

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Gust

Finney

Li³

et al. 2019

Annals of Neurology

130

178

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Objective: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. Methods: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Results: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calciumbinding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Interpretation: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury.

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“…Our dosing strategy for tocilizumab is 12 mg/kg for patients with a weight less than 30 kg or 8 mg/kg for weight greater than 30 kg with a maximum dose of 800 mg. This is in accordance with the FDA guidelines . This dose may be administered repeatedly every 8 hours over the first 24 hours and for a maximum of four doses total if there is continued decline in clinical status.…”

Section: Cytokine Release Syndromementioning

confidence: 77%

Cellular therapy: Immune‐related complications

Oved

Barrett

Teachey

2019

Immunological Reviews

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The advent of chimeric antigen receptor T (CAR‐T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized “living therapy” is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR‐T. The overwhelming release of cytokines and chemokines by activated CAR‐T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti‐IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR‐T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR‐T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR‐T‐related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR‐T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR‐T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.

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FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome

Abstract: This article summarizes key review findings that supported the approval of tocilizumab for treatment of severe or life‐threatening CAR T cell‐induced cytokine release syndrome.

Cited by 683 publications

References 20 publications

A review of cancer immunotherapy toxicity

A review of cancer immunotherapy toxicity

Glial injury in neurotoxicity after pediatric CD19‐directed chimeric antigen receptor T cell therapy

Cellular therapy: Immune‐related complications

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