Cytokines in CAR T Cell-Associated Neurotoxicity.
Juliane Gust,Juliane Gust,Rafael Ponce,W. Conrad Liles,Gwenn A. Garden,Cameron J. Turtle,Cameron J. Turtle +6 more
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In this article, the authors systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy.Abstract:
Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.read more
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A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains.
TL;DR: In this article, the authors compared the efficacy and toxicity profiles associated with CARs containing either CD28 or 4-1BB costimulatory domains and found that the rates of neurological toxicities were higher with CD28-costimulated CARs, although this finding is probably the result of a combination of factors rather than due to CD28 signalling alone.
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TL;DR: In this article, the authors discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM.
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Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies.
TL;DR: In this paper, the authors summarized the mechanisms underlying CRS and ICANS and provided potential treatment and prevention strategies for CAR T-cell therapy, and proposed a treatment strategy for CRS.
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Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies
TL;DR: McNerney et al. as mentioned in this paper showed that blocking IFNγ in CAR T cells does not impair their cytotoxicity against hematologic tumor cells and paradoxically enhances their proliferation and reduces macrophage-mediated cytokines and chemokines associated with CRS.
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CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges
TL;DR: This review focuses on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets,CAR-T related toxicities, and resistance to CAR- T cell therapy, and provides some practical recommendations.
References
More filters
Journal ArticleDOI
Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma (R/R LBCL)
Max S. Topp,Tom van Meerten,Roch Houot,Monique C. Minnema,Noel Milpied,Pieternella J. Lugtenburg,Catherine Thieblemont,Martin Wermke,Kevin W. Song,Irit Avivi,John Kuruvilla,Ulrich Dührsen,Rachel Chu,Lianqing Zheng,Vicki Plaks,Anne Kerber,Marie José Kersten +16 more
TL;DR: Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy and levels of key NE-associated biomarkers appeared lower in C4 than in C1+2.
Journal ArticleDOI
Risk-Adapted Preemptive Tocilizumab Decreases Severe Cytokine Release Syndrome (CRS) after CTL019 CD19-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Regina M. Myers,Stephan Kadauke,Yimei Li,Yimei Li,Colleen Callahan,Whitney L. Gladney,Julie C. Fitzgerald,Lisa Wray,Allison Barz Leahy,Diane Baniewicz,Laura S Motley,Regina McGuire,Vikram Shenoy,David M. Barrett,David T. Teachey,Shannon L. Maude,Amanda M. DiNofia,Stephan A. Grupp +17 more
TL;DR: Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate, without impact on complete remission rate.
Journal ArticleDOI
Acute lethal encephalopathy in systemic juvenile rheumatoid arthritis
TL;DR: A first patient with systemic juvenile rheumatoid arthritis is presented in which acute necrotizing encephalopathy developed as a complication of macrophage activation syndrome but not of Reye's syndrome.
Journal ArticleDOI
Comparison of the inflammatory response of brain microvascular and peripheral endothelial cells following infection with Neisseria meningitidis.
TL;DR: Peripheral and brain microvascular endothelial cells differentially release IL‐8, IL‐6 and MCP‐1 upon infection with Neisseria meningitidis, which is a critical event in the development of invasive meningococcal disease.
Book ChapterDOI
Neurotoxicities After CAR T-Cell Immunotherapy
TL;DR: Data from patients and animal models of neurotoxicity demonstrate high levels of key cytokines in the blood and cerebrospinal fluid, and monocyte/macrophage and endothelial cell activation with compromise of the blood-brain barrier appears to contribute to the pathogenesis.
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