Ann Lab Med.  2024 May;44(3):210-221. 10.3343/alm.2023.0388.

Current Challenges in Chimeric Antigen Receptor T-cell Therapy in Patients With B-cell Lymphoid Malignancies

• Kim SJ
• Yoon SE
• Kim WS

• KMID: 2555684
• DOI: http://doi.org/10.3343/alm.2023.0388

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy based on genetically engineered T cells derived from patients. The introduction of CAR T-cell therapy has changed the treatment paradigm of patients with B-cell lymphoid malignancies. However, challenging issues including managing life-threatening toxicities related to CAR T-cell infusion and resistance to CAR T-cell therapy, leading to progression or relapse, remain. This review summarizes the issues with currently approved CAR T-cell therapies for patients with relapsed or refractory B-cell lymphoid malignancies, including lymphoma and myeloma. We focus on unique toxicities after CAR T-cell therapy, such as cytokine-related events and hematological toxicities, and the mechanisms underlying post-CAR T-cell failure.

Keyword

Chimeric antigen receptor; Cytokine toxicity; Efficacy; Lymphoma; Multiple myeloma

Figure

• 

  Fig. 1 Currently approved CAR T-cell products and their indications. Abbreviations: CAR, chimeric antigen receptor; r/r, relapsed or refractory; DLBCL, diffuse large B-cell lymphoma; HGBCL, high-grade B-cell lymphoma; PMBCL, primary mediastinal large B-cell lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma; tFL, transformed follicular lymphoma; B-ALL, B-acute lymphoblastic leukemia; MM, multiple myeloma.

• 

  Fig. 2 Steps in the process of CAR T-cell therapy. (1) Physicians should select patients who are appropriate for CAR T-cell therapy. (2) Autologous T cells should be collected via a qualified process. (3) Patients may need various bridging therapies during CAR T-cell manufacturing. (4) Patients receive CAR T cells after lymphodepletion chemotherapy, and the CAR T-cell therapy center should establish standardized protocols for monitoring and managing toxicities after CAR T-cell therapy. Abbreviation: CAR, chimeric antigen receptor.

• 

  Fig. 3 Guidance for assessing hematological toxicity after CAR T-cell therapy. In the CAR-HEMATOTOX model, low platelet count, high ferritin level, low absolute neutrophil count, low Hb level, and high CRP level are risk factors for hematologic toxicity. Based on the sum of scores, high or low risk can be determined. Based on the ICAHT grading system, early and late ICAHT can be determined according to the time after CAR T-cell infusion. Abbreviations: CAR, chimeric antigen receptor; ICAHT, immune effector cell-associated hematotoxicity; EHA, European Hematology Association; EBMT, European Society for Blood and Marrow Transplantation; CRP, C-reactive protein; ANC, absolute neutrophil count.

• 

  Fig. 4 Differentiation of T cells and its potential influence on the efficacy of CAR T cells. The proportions of memory stem and central memory T cells may be related to the persistence of CAR T cells, leading to higher antitumor efficacy. Abbreviation: CAR, chimeric antigen receptor.

Reference

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