Elsevier

Blood Reviews

Volume 34, March 2019, Pages 45-55
Blood Reviews

Review
Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management

https://doi.org/10.1016/j.blre.2018.11.002Get rights and content

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Two CAR T-cell products are now approved for clinical use by the U.S. FDA: tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical activity has been generated. A barrier to widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity. Manifestations of CRS include fevers, hypotension, hypoxia, end organ dysfunction, cytopenias, coagulopathy, and hemophagocytic lymphohistiocytosis. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasias, seizures, and cerebral edema. Our understanding of the pathophysiology of CRS and neurotoxicity is continually improving. Early and peak levels of certain cytokines, peak blood CAR T-cell levels, patient disease burden, conditioning chemotherapy, CAR T-cell dose, endothelial activation, and CAR design are all factors that may influence toxicity. Multiple grading systems for CAR T-cell toxicity are in use; a universal grading system is needed so that CAR T-cell products can be compared across studies. Guidelines for toxicity management vary among centers, but typically include supportive care, plus immunosuppression with tocilizumab or corticosteroids administered for severe toxicity. Gaining a better understanding of CAR T-cell toxicities and developing new therapies for these toxicities are active areas of laboratory research. Further clinical investigation of CAR T-cell toxicity is also needed. In this review, we present guidelines for management of CRS and CAR neurotoxicity.

Section snippets

Introduction to CAR T-cell therapy

A chimeric antigen receptor (CAR) is a fusion protein comprised of an antigen recognition moiety and T-cell signaling domains [[1], [2], [3], [4], [5], [6]]. Clinical trials of CAR T cells targeting the B-cell marker CD19 have shown clear efficacy in multiple hematologic malignancies, including ALL [[7], [8], [9], [10], [11], [12], [13]], chronic lymphocytic leukemia (CLL) [[14], [15], [16], [17]], and non-Hodgkin lymphoma (NHL) [[18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]

Clinical manifestations of CAR T-cell toxicity

The first presenting symptom of CRS is usually fever [9,14,20,42], which can occur hours to several days following cell infusion [9,11]. In a clinical trial of anti-CD19 CAR T cells for ALL, patients initially developed fever as early as the day of infusion and as late as 9 days after cell infusion [9]. Similarly, in our experience, patients usually experience the first signs of CRS within 14 days following CAR T-cell infusion, though infrequent cases of delayed CRS are possible. CRS in our

Factors contributing to CAR T-cell toxicity

CRS is an inflammatory syndrome caused by multiple cytokines produced by the CAR T cells themselves and by other cells. Cytokines and inflammatory markers associated with more severe CRS include C-reactive protein (CRP), ferritin, interferon (IFN)-ϒ, interleukin (IL)-1, IL-2, soluble IL2Rα, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, granzyme B, granulocyte/macrophage colony stimulating factor (GM-CSF), soluble gp130, macrophage inflammatory protein-1α (MIP-1α) and monocyte

CAR T-cell toxicity grading systems

Multiple systems have been used to grade CRS and neurologic toxicity (Table 2). A consensus group grading system published by Lee and colleagues in 2014 first attempted to provide a unified grading system for CRS [42]. The Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania, and the CAR-T-cell therapy-associated toxicity (CARTOX) Working Group (CARTOX group) have also published their own grading systems for CRS [[11], [12], [13], [14],43]. However, the grading systems

Management approaches for CAR T-cell toxicity across institutions

Guidelines for supportive care for hospitalized patients following CAR T-cell infusion are similar with minor variations among treatment centers, with an emphasis on frequent vital signs, neurologic assessment, and frequent monitoring of blood counts, electrolytes, coagulation assays, and inflammatory markers [41,43]. However, there is variability among centers and among cell products as to preference of administering the product on an inpatient or outpatient basis. Tisagenlecleucel has been

Recommendations for management of CAR T-cell toxicities

The initial evaluation and management of patients experiencing CAR T-cell related toxicity and supportive care guidelines used by the authors when treating adult patients at the National Cancer Institute are summarized in Table 4. Our guidelines for administering immunosuppression for toxicity are summarized in Fig. 1. These guidelines are written for adult patients and are not meant to be applied to pediatric patients. Because CAR T cells are a new therapy and because different CAR T-cell

Future considerations

The CAR T-cell field is still quite new, and, likewise, the management of CAR T-cell toxicities is in its early stage. Toxicity management is certain to change significantly in the coming years as more data become available. The development of universal grading scales for CRS and neurologic toxicity is an essential step in building generalizable guidelines for managing toxicity. Risk-adapted strategies for tailoring CAR T-cell dose based on malignancy burden and expected in vivo antigen

Conclusions

CAR T-cell therapy is a great advance in the treatment of hematologic malignancies. While CRS and neurologic toxicity remain barriers to widespread use of this therapy, improved understanding of the pathophysiology of these processes will aid in the development of optimum strategies of immunosuppression and supportive care.

  • 1.

    Practice Points

    • Mild to moderate CRS and neurologic toxicities may resolve without intervention with immunosuppression. However, severe CRS and neurologic toxicities may be

Conflict of interest statement

Jennifer Brudno: no conflicts to disclose.

James Kochenderfer: research funding from Kite, a Gilead Company and Celgene, Inc. Multiple patents and royalties related to CAR T-cell therapy.

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