Elsevier

The Lancet Haematology

Volume 8, Issue 3, March 2021, Pages e216-e228
The Lancet Haematology

Review
Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: is there an excess risk for infection?

https://doi.org/10.1016/S2352-3026(20)30376-8Get rights and content

Summary

Therapy with genetically engineered chimeric antigen receptor (CAR) T cells targeting the CD19 antigen is promising for a number of refractory or relapsed B-cell malignancies. Information on the infectious complications of this immunotherapeutic strategy is scarce and difficult to interpret, as many factors influence infection incidence and outcomes. CAR T-cell therapy is usually given to patients with haematological cancers who have been heavily pretreated and are severely immunosuppressed. Moreover, the risk of infection is increased by the administration of lymphodepleting chemotherapy before CAR T-cell infusion, and by the development of complications such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, which are managed with anti-interleukin-6 antibodies, or corticosteroids, or both. On-target, off-tumour toxicities, such as B-cell aplasia, hypogammaglobulinaemia, and persistent or biphasic cytopenia, are common. In this Review, we evaluate the reported infectious complications of CAR T-cell therapy and associated risk factors and offer perspectives on its infection risk.

Introduction

Cellular immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) has rapidly emerged as a promising new treatment for a broad range of cancers, particularly lymphoid malignancies. Now, a new generation of CAR T cells with improved efficacy and safety has been designed.1, 2 The impressive results obtained in patients with CD19+ B-cell malignancies treated with second-generation anti-CD19 CAR T cells led to US Food and Drug Administration approval of two of these therapies: tisagenlecleucel for the treatment of young adults with relapsed or refractory B-cell acute lymphocytic leukaemia, and tisagenlecleucel or axicabtagene ciloleucel for the treatment of adults with some types of relapsed or refractory large B-cell lymphoma.3, 4, 5 Approval for a third product, lisocabtagene maraleucel (also known as liso-cel or JCAR017), is expected during 2020.2 Anti-CD19 CAR T-cell therapy, has also shown high overall response rates in patients with other B-cell non-Hodgkin lymphomas.2, 6 Products targeting antigens other than CD19 are being investigated in patients with other haematological malignancies or solid tumours.7

Patients receiving CAR T-cell therapy might be at an increased risk for infection because of several factors,8 including the cumulative immunosuppression associated with the underlying malignant disease and its previous treatment, and the cytotoxic and lymphodepleting chemotherapy administered before cell infusion.9 In addition, CAR T-cell infusion depletes normal CD19+ B cells, potentially resulting in protracted hypogammaglobulinaemia.10 Finally, preliminary data show that CAR T-cell therapy might directly cause protracted cytopenia via a chemokine-mediated mechanism.

Importantly, the two most frequent and feared treatment-related toxic effects of CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are associated with substantial immunosuppression. CRS is usually low grade, with reported incidences ranging from 43% to 65%,3, 4, 5 and can be safely managed with supportive care and, rarely, tocilizumab (an anti-interleukin [IL]-6 monoclonal antibody approved for rheumatoid arthritis treatment). However, ICANS is commonly high grade (in 35–65% of cases)3, 4, 5 and only treatable with corticosteroids. Accordingly, the current management of CAR T-cell therapy-associated toxicity also increases the risk of infection.9, 10, 11 The figure depicts the most common CAR T-cell therapy-associated immunosuppression and infection risk factors.

In this Review, we offer perspectives on the infectious complications of anti-CD19 CAR T-cell therapy for the treatment of lymphoid malignancies. Specifically, we provide an overview of the infection risks related to the lymphodepleting conditioning regimens used in these patients, the type and status of the underlying malignancy, and the potential immunosuppressive effect from the treatment of CAR T-cell therapy toxicities. We seek to discuss this complex area in the contest of available recommendations regarding anti-infective prophylaxis in these patients (published by the European Society for Blood and Marrow Transplantation [EBMT] and the Joint Accreditation Committee of the International Society for Cell and Gene Therapy).12 Our goal is to provide a conceptual framework for developing future prediction models to stratify by risk patients with lymphoid malignancies treated with CAR T-cell therapy, to improve infection management in this challenging group of patients.

Section snippets

Infectious complications of CAR T-cell therapy

Studies of the infectious complications related to CAR T-cell therapy are scarce and difficult to interpret because of their retrospective single-centre design and differences in patients' characteristics, CAR T-cell therapy doses and administration schedules, antimicrobial prophylaxis use, and diagnostic approaches (table 1 and table 2).13, 14, 15, 16, 17, 18, 19

The largest case series consisted of 133 adult patients with relapsed or refractory CD19+ acute lymphocytic leukaemia, chronic

Risk factors associated with infectious complications of CAR T-cell therapy

Some of the reported risk factors associated with infection are related to the host's immune system before CAR T-cell therapy. Other factors are directly associated with the use of lymphodepleting chemotherapy either before cell infusion or with the infusion of cells (panel 1).

Differentiating infection from CAR T-cell therapy toxicity

Fever, malaise, anorexia, and myalgia are features of CRS and, in severe cases, CRS can mimic a sepsis-like syndrome with hypotension, hypoxia, and multiorgan dysfunction. Also, CAR T-cell therapy-associated ICANS can mimic infectious encephalitis, interfering in the management of this complication. Beyond sepsis-like and encephalitis-like syndromes, CAR T-cell therapy-associated CRS rarely mimics infections in other organs, posing a great diagnostic dilemma.9, 10, 62, 63, 64, 65 Thus, it is

Future perspectives

Several clinical research questions regarding CAR T-cell therapy and infections remain (panel 3). For example, with the development of new generations of CAR T cells, researchers will need to determine whether these new CAR products are associated with a reduced or greater risk of infection than earlier products. CAR T cells can be engineered with safety switches to turn off immunotherapy, which include suicide genes, combinatorial target-antigen recognition, synthetic Notch receptors,

Search strategy and selection criteria

We searched PubMed and MEDLINE for articles that were published between Jan 1, 2007, and June 30, 2020, using the search terms “CAR-T cell therapy”, “CAR”, “chimeric antigen receptor”, “cellular immunotherapy”, “immune reconstitution”, “complications”, “adverse events”, “side effects”, “infection”, “reactivation”, and “infectious complications.” Articles resulting from these searches, and relevant references cited in those articles, were reviewed. Only articles published in English were

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      Citation Excerpt :

      However, understanding the infection risk of CAR-T therapy is complicated due to the multi-faceted nature of the immunosuppression involved. Infection risk may be heightened due to the immunosuppressive conditioning regimens prior to CAR-T therapy, the CAR-T product itself, and the potential adverse events of CAR-T therapy (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]), which may increase infection risk but also require management with corticosteroids, further heightening potential infection risk (Gudiol et al., 2021). Hypogammaglobulinemia resulting from B-cell aplasia may be a common adverse event of CAR-T therapy, though this remains poorly understood, as reported rates vary due to the heterogeneity of study methods and definitions (Hill et al., 2019).

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