Abstract
Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.
Highlights
Chimeric antigen receptor (CAR) T-cell therapy, one of the most significant developments in immunotherapy, has yielded impressive outcomes in hematological malignancies
CARChimeric antigen receptor, N number of patients, complete remission (CR) Complete remission, cytokine release syndrome (CRS) Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) Immune effector cell-associated neurotoxicity syndrome, Refs References, acute lymphocyte leukemia (ALL) Acute lymphoblastic leukemia, non-Hodgkin lymphoma (NHL) Non-Hodgkin lymphoma, MCL Mantle cell lymphoma, Relapse or refractory multiple myeloma (MM) Multiple myeloma, chronic lymphocytic leukemia (CLL) Chronic lymphocytic leukemia, NR No report, m Months, d Days, h Hours, Cy Cyclophosphamide, Flu Fludarabine, E Etoposide CRS and ICANS grading systems used by each trial are denoted by superscripts as follows: A American Society for Transplantation and Cellular Therapy (ASTCT) criteria, C CTCAE criteria, L Lee criteria, P PENN/CHOP criteria, M MSKCC criteria * Severe CRS/ICANS are defined as CRS/ICANS ≥ Grade 3 † Modified criteria ‡ 25 m 50% vs 6.3 m 50% (Cy/Flu Group vs Cy or Cy/E Group) § Progression-free survival ¶ Event-free survival
CAR-T Chimeric antigen receptor T cell, CRS Cytokine release syndrome, ICANS Immune effector cell associated neurotoxicity syndrome, IL Interleukin, FDA US Food and Drug Administration, NA Not applicable, granulocytemacrophage colony-stimulating factor (GM-CSF) Granulocyte-macrophage colony-stimulating factor, JAK Janus kinase, STATSignal transducer and activator of transcription, TK Tyrosine kinase, lymphocyte-specific protein tyrosine kinase (LCK) Lymphocyte-specific protein tyrosine kinase, ITK IL-2-induced tyrosine kinase, TNF-α Tumor necrosis factor-α, cyclin-dependent kinase 7 (CDK7) Cyclindependent kinase 7 corticosteroids could maintain the intact efficacy of CAR T-cell therapy
Summary
Chimeric antigen receptor (CAR) T-cell therapy, one of the most significant developments in immunotherapy, has yielded impressive outcomes in hematological malignancies. The most common toxicity is cytokine release syndrome (CRS), which is a systemic inflammatory response mediated by the overactivation of effector cells and large amounts of cytokines [6] Neurotoxicity, another common toxicity related to CAR T-cell therapy, is a toxic encephalopathy state with a broad spectrum of neuropsychiatric symptoms. It is believed that CRS is a systemic disease induced by the overactivation of immune effector cells and supraphysiological levels of various proinflammatory cytokines, including IL-1, IL-6, IFN-γ, and granulocytemacrophage colony-stimulating factor (GM-CSF) [7] This toxicity manifests as a constellation of symptoms (Table 2), most of which are reversible; 0–9.1% of patients progressed to fatal cases (Table 1), whereas there were no deaths from CRS in most clinical trials. N Target Costimu- CR (%) Overall survival CRS and ICANS latory rate grading criteria domain
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