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Review
. 2025 May 1;17(1):e2025039.
doi: 10.4084/MJHID.2025.039. eCollection 2025.

Toxicities Associated with CAR-T Cell Therapies

Ugo Testa  1 , Germana Castelli  1 , Elvira Pelosi  1 , Eugenio Galli  2 , Patrizia Chiusolo  2
Affiliations
Review

Toxicities Associated with CAR-T Cell Therapies

Ugo Testa et al. Mediterr J Hematol Infect Dis. .

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has improved the outcomes of patients with relapsed/refractory B-cell lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, CAR-T cell therapy is also associated with distinct toxicities that contribute to morbidity and mortality. A large number of studies now define the different toxicities associated with CAR-T cell therapy and have, in part, clarified their mechanisms. In particular, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two main acute toxicity events that occur after CAR-T cell infusion. Other CAR-T-related toxicities occur later after CAR-T cell infusion and include B-cell aplasia, hypogammaglobulinemia, infections, and cytopenias. Infections represent the main cause of non-relapse death observed in patients undergoing CAR-T cell therapy. Second primary malignancies are rare and are mainly represented by myeloid malignancies.

Keywords: Diagnosis; Heparin-binding protein; Infectious disease; Meta-analysis; Mortality; Organ failure; Prognosis; Sepsis; Systematic review.

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Conflict of interest statement

Competing interests: The authors declare no conflict of Interest.

Figures

Figure 1
Figure 1
Timing of the main CAR-T cell-related adverse events. Approximate timeline of occurrence of main toxicities related to CAR-T cell infusion; for each of these toxicities, the typical time of onset is underlined by the start of each bar, the time to resolution by the end of the bar, and the duration by the length of the bar.
Figure 2
Figure 2
Acute toxicities (CRS and ICANS) occurring after CAR-T cell therapy. The period of first months after CAR-T cell infusion is subdivided into 5 phases, according to Morris et al. The timing of CRS and ICANS development is outlined, indicating the most frequent times of CRS and ICANS peaks. Also, the kinetics of the production of groups of cytokines at different times after CRA-T cell infusion are shown.
Figure 3
Figure 3
Correlation between the frequency of the occurrence of ICANS and CRS observed in the major clinical trials carried out with commercial CD19-CAR-T cells: left up panel: all ICANS and CRS events; right up panel: grade ≥3 ICANS and grade ≥3 CRS. Incidence of CRS and ICANS in clinical trials involving CD19-CAR-T cells containing CD28 or 4-1BB costimulatory domains: left down panel: all CRS and all ICANS; right down panel: grade ≥3 CRS and ICANS events.
See this image and copyright information in PMC

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