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Review
. 2022 Oct 14:13:950923.
doi: 10.3389/fphar.2022.950923. eCollection 2022.

The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions

Yanping Li  1 , Yue Ming  1 , Ruoqiu Fu  1 , Chen Li  1 , Yuanlin Wu  1 , Tingting Jiang  1 , Ziwei Li  1 , Rui Ni  1 , Li Li  1 , Hui Su  1 , Yao Liu  1
Affiliations
Review

The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions

Yanping Li et al. Front Pharmacol. .

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is effective in the treatment of refractory/relapsed (r/r) hematological malignancies (r/r B-cell lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma). In addition, it is being explored as a treatment option for solid tumors. As of 31 March 2022, seven CAR-T therapies for hematological malignancies have been approved worldwide. Although CAR-T therapy is an effective treatment for many malignancies, it also causes adverse effects. The incidence of cytokine release syndrome (CRS), the most common adverse reaction after infusion of CAR-T cells, is as high as 93%.CRS, is the leading risk factor of immune effector cell-associated neurotoxicity syndrome (ICANS), as well as cardiovascular, hematological, hepatorenal, skin, pulmonary, and gastrointestinal toxicity. Severe adverse reactions complicated by CRS severely impede the widespread application of CAR-T therapy. The CAR-T product was initially approved in 2017; however, only limited studies have investigated the adverse reactions owing to CAR-T therapy compared to that of clinically approved drugs. Thus, we aimed to elucidate the mechanisms, risk factors, diagnostic criteria, and treatment of toxicities concurrent with CRS, thereby providing a valuable reference for the safe, effective, and widespread application of CAR-T therapy.

Keywords: CAR-T cell therapy; ICANS; consensus grading; cytokine release syndrome; organ system toxicity; treatment strategies.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Toxicities during CAR-T therapy. (A) The structure of CAR. (B) Pathogenesis of CRS. (C) Organ systemic toxicities induced by CRS. Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; scFv, single-chain variable fragment; IL, interleukin; IFN-γ, interferon gamma; GM-CSF, granulocyte macrophage colony-stimulating factor; TNF-α, tumor necrosis factor alpha. This figure created with BioRender.com.
FIGURE 2
FIGURE 2
Pathogenesis of ICANS during CAR-T therapy. Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; IL, interleukin; IFN-γ, interferon gamma; GM-CSF, granulocyte macrophage colony-stimulating factor; TNF-α, tumor necrosis factor alpha; BBB, blood brain barrier. This figure created with BioRender.com.
FIGURE 3
FIGURE 3
Pathogenesis of cardiovascular toxicity during CAR-T therapy. Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IL, interleukin; TNF-α, tumor necrosis factor alpha; MAPK, mitogen-activated protein kinase; TLS, tumor lysis syndrome; DIC, disseminated intravascular coagulation; Ang-2, angiopoietin-2; VWF, von willebrand factor. This figure created with BioRender.com.
See this image and copyright information in PMC

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