Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques

Nellan, Anandani; McCully, Cynthia; Garcia, Rafael Cruz; Jayaprakash, Nalini; Widemann, Brigitte C.; Lee, Daniel W.; Warren, Katherine E.

doi:10.1182/blood-2018-05-846428

Cited by 89 publications

(54 citation statements)

References 14 publications

(9 reference statements)

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“…Unlike the classic symptoms of CRS, immune effector cell-associated neurotoxicities do not usually respond to tocilizumab, which is not surprising given the observation that i.v. tocilizumab administration does not generate significant levels of the drug in the cerebrospinal fluid [26]. Given this finding, along with the paucity of mechanistic data, the lack of known CD19 expression in the CNS, and the propensity for neurotoxicities to develop well after the classic symptoms of CRS have resolved, we conclude that immune effector cell-associated neurotoxicities should be excluded from the definition of CRS.…”

Section: Toxicities Excluded From the Definition Of Crsmentioning

confidence: 86%

“…In a recent report, Gust et al [30] suggested a role for endothelial activation and blood-brain barrier disruption in the pathophysiology of neurotoxicity. Another report found elevated levels of the excitatory NMDA receptor agonists glutamate and quinolinic acid in cerebrospinal fluid from patients with neurotoxicity [26]. Several reports suggest a role for proinflammatory cytokines and myeloid cells besides activated T cells [2,18,29,[31][32][33].…”

Section: Definition Of Icansmentioning

confidence: 99%

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ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Lee

Santomasso

Locke

et al. 2019

Biology of Blood and Marrow Transplantation

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1,824

1,619

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Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell-and bispecific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

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Section: Toxicities Excluded From the Definition Of Crsmentioning

confidence: 86%

Section: Definition Of Icansmentioning

confidence: 99%

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Lee

Santomasso

Locke

et al. 2019

Biology of Blood and Marrow Transplantation

Self Cite

1,824

1,619

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“…After IL6R blockade with tocilizumab, IL6 levels in the serum continue to rise, which could lead to ongoing exposure of the brain parenchyma to IL6. In a non‐human primate preclinical model, intravenous administration of tocilizumab provided minimal central nervous system (CNS)/CSF exposure to the drug, whereas intraventricular administration increased the CSF concentration of tocilizumab by approximately 85‐fold (Nellan et al , ). However, it is currently unclear if intraventricular administration in patients would be helpful to reduce neurotoxicity severity.…”

Section: Management Of Crs and Neurotoxicitymentioning

confidence: 99%

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

Hay

2018

Br J Haematol

140

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Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

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“…27,39 In fact, use of tocilizumab increases serum IL-6 concentration by interfering with IL-6 clearance through uptake in peripheral tissues. 31 43 Thus, its use in patients experiencing neurotoxicity may be detrimental. 40,44 The most severe manifestations of neurotoxicity include refractory seizure activity and life-threatening cerebral edema.…”

Section: Toxicities From Car T Therapymentioning

confidence: 99%

Next Generation of Cancer Treatments: Chimeric Antigen Receptor T-Cell Therapy and Its Related Toxicities: A Review for Perioperative Physicians

Echeverry

Fischer

Mead

2019

Anesthesia &Amp; Analgesia

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Cancer immunotherapy has entered a new era with the recent introduction of genetically engineered T-cells that express chimeric antigen receptors (CARs) capable of recognizing and destroying tumor cells. Several clinical trials in patients with relapsed or refractory B-cell malignancies have demonstrated complete remission rates ranging from 50% to 90%, with long-term data suggestive of a possible curative response. CAR T-cell therapy is currently under investigation for earlier use in these disease processes and in various other solid and liquid tumors. CAR T-cell therapy is associated with a unique postinfusion toxicity profile including cytokine-release syndrome and neurotoxicity. These toxicities are usually reversible but can be fatal, requiring close vigilance and prompt treatment often in an intensive care unit (ICU) setting. CAR T-cell therapy is currently restricted to designated centers possessing expertise in acute toxicity management, but wider use is likely if early therapeutic successes are replicated. As perioperative and critical care physicians, anesthesiologists may encounter such patients in the perioperative or ICU setting and should become familiar with this unique and novel therapeutic modality capable of causing extreme cardiovascular and respiratory compromise. This review will describe the immunobiology of CAR T-cells, their relevance to cancer treatment, clinical aspects of their therapeutic use in cancer chemotherapy, toxicities related to CAR T-cell use, and their therapeutic management.

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Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques

Cited by 89 publications

References 14 publications

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

Next Generation of Cancer Treatments: Chimeric Antigen Receptor T-Cell Therapy and Its Related Toxicities: A Review for Perioperative Physicians

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