Mitigation and Management of Common Toxicities Associated with the Administration of CAR-T Therapies in Oncology Patients

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapies are one of the main approaches among targeted cellular therapies. Despite the potential benefit and durable responses observed in some patients receiving CAR-T therapies, serious and potentially fatal toxicities remain a major challenge. The most common CAR-T-associated toxicities include cytokine release syndrome (CRS), neurotoxicity, cytopenias, and infections. While CRS and neurotoxicity are generally managed with tocilizumab and corticosteroids, respectively, high-grade toxicities can be life-threatening. Close postinfusion monitoring and assessment of clinical laboratory parameters, patient-related and clinical risk factors (e.g., age, tumor burden, comorbidities, baseline laboratory parameters, and underlying abnormalities), and therapy-related risk factors (e.g., CAR-T type, dose, and CAR-T-induced toxicity) are effective strategies to mitigate the toxicities. Clinical laboratory parameters, including various cytokines, have been identified for CRS (interleukin [IL]-1, IL-2, IL-5, IL-6, IL-8, IL-10, C-reactive protein [CRP], interferon [IFN]-γ, ferritin, granulocyte-macrophage colony-stimulating factor [GM-CSF], and monocyte chemoattractant protein-1), neurotoxicity (IL-1, IL-2, IL-6, IL-15, tumor necrosis factor [TNF]-α, GM-CSF, and IFN-γ), cytopenias (IL-2, IL-4, IL-6, IL-10, IFN-γ, ferritin, and CRP), and infections (IL-8, IL-1β, CRP, IFN-γ, and procalcitonin). CAR-T-associated toxicities can be monitored and treated to mitigate the risk to patients. Assessment of alterations in clinical laboratory parameter values that are correlated with CAR-T-associated toxicities may predict development and/or severity of a given toxicity, which can improve patient management strategies and ultimately enable the patients to better tolerate these therapies.

Fig. 1

T-cell therapy patient journey. (1) Before receiving T-cell therapy, patient eligibility for treatment is assessed by a multi-disciplinary team; initial evaluations include medical history, performance status, screening laboratory tests, and imaging. (2) Following leukapheresis, T cells are shipped to a laboratory for processing. (3) T cells are isolated and activated. Activated T cells are genetically engineered, expanded, and then cryopreserved before being reintroduced into the patient. (4) Prior to infusion, the patient undergoes lymphodepletion to ensure effective CAR-T expansion and cytotoxic impact. Lymphodepletion is routinely performed with a combination of fludarabine and cyclophosphamide. (5) Modified T cells are injected back into the patient via infusion. (6) Following the infusion, patients are closely monitored for 2–4 weeks for potential toxicities with regular medical assessments thereafter

Fig. 2

Overview of the main toxicities associated with CAR-T therapies. CAR-T; chimeric antigen receptor T cell; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome

Fig. 3

Incidence and severity of the most common toxicities associated with CAR-T therapies. The circles represent the incidence reported in individual studies. Data sources are listed in Electronic Supplementary Material 1; the individual studies were published between 2014 and 2023 for CRS and ICANS, and between 2017 and 2023 for cytopenias and infections. CAR-T; chimeric antigen receptor T cell; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome

Fig. 4

Clinical laboratory parameters correlated with the risk of developing CAR-T-associated toxicities. Ang, angiopoietin; CA, catecholamines; CAR-T, chimeric antigen receptor T cell; CRP, C-reactive protein; CRS, cytokine release syndrome; F, factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; ICANS, immune effector cell-associated neurotoxicity syndrome; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; pTF, plasma tissue factor; sE-selectin, soluble E-selectin; sICAM, soluble intercellular adhesion molecule; TNF, tumor necrosis factor; VCAM, vascular-cell adhesion molecule; vWF, von Willebrand factor

Fig. 5

Sequence of events leading to cytokine release syndrome, adapted from Cosenza et al. Int J Mol Sci. 2021;22:7652 [49]. CAR-T cells bind to the tumor cells and induce the release of cytokines such as IFN-γ or TNF-α, leading to the activation of bystander immune and non-immune cells, which further release proinflammatory cytokines, triggering a cascade reaction in which high levels of released IL-6 activate T cells and other immune cells, leading to a cytokine storm. CAR-T, chimeric antigen receptor T cell; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; NK, natural killer; TNF, tumor necrosis factor

Fig. 6

Pathophysiology of immune effector cell-associated neurotoxicity syndrome, adapted from Morris et al. Nat Rev Immunol. 2022; 22(2):85-96 [105]. Infused CAR-T cells and other activated host immune cells release proinflammatory cytokines leading to activation of endothelial cells and disruption of the BBB; increased permeability of the BBB facilitates infiltration of CAR-T cells and cytokines into the CNS, triggering inflammation and microglial activation, leading to abnormal neuronal function. BBB, blood–brain barrier; CAR-T, chimeric antigen receptor T cell; CNS, central nervous system