A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy

Cai, Changjing; Tang, Dongxing; Han, Ying; Shen, Edward; Ahmed, Omar; Guo, Cao; Shen, Hong; Zeng, Shan

doi:10.18632/aging.104058

Cited by 30 publications

(22 citation statements)

References 47 publications

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“…Among them, the number of reports following tisagenlecleucel, axi-cel, liso-cel, and KTE-X19 were 893 (58.83%), and 562 (37.02%), 25 (1.65%), 38 (2.50%), respectively (Table 1). Likewise, gastrointestinal disorders were also reported in previous real-world study (25). Cai et al reported the rates of GIAEs were 13% and 10% following tisagenlecleucel and axicel infusion, respectively.…”

Section: Discussionsupporting

confidence: 66%

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Song

Liu

et al. 2022

Preprint

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Clinical trials are underpowered to detect infrequent toxicities following chimeric antigen receptor T-cell (CAR-T) therapy such as gastrointestinal adverse events (GIAEs). Here, we extensively revealed the GIAEs following four U.S. Food and Drug Administration (FDA)-approved CD19-targeted CAR-T products using FDA adverse event reporting system, tisagenlecleucel, axicabtagene-ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel. The disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC) and the lower bounds of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero were deemed significant, respectively. Among 105,087,611 reports in FAERS between January 2017 and December 2021, 1518 CAR-T-associated GIAEs reports were identified. 23 GIAEs (n = 281, 18.51%) were significantly overreported following CAR-T therapy compared with the full database, of which 11 GIAEs (n = 156, 10.28%) were associated with gastrointestinal infection such as clostridium difficile colitis (n = 44 [2.90%], ROR = 5.55 [95% CI: 4.12-7.46]), enterovirus infection (n = 23 [1.52%], ROR = 20.02 [13.15-30.48]), and mucormycosis (n = 15 [0.99%], ROR = 5.13 [3.09-8.54], all IC025 > 0). Overall, the fatality rate of 11 overreported infection-related GIAEs was 29.49%, which was higher following tisagenlecleucel compared with axicabtagene-ciloleucel (31.45% vs. 24.14%). In this largest post-marketing study to date, we firstly analyzed the CAR-T-associated GIAEs comprehensively and found that gastrointestinal infections were underestimated but led to substantial mortality in CAR-T recipients, which provided a deeper understanding of CAR-T therapy and early alert of those rare but life-threatening GIAEs for the clinician.

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Section: Discussionsupporting

confidence: 66%

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Song

Liu

et al. 2022

Preprint

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“…Ever since the amazing results obtained by Coley’s Toxin, adverse effects (AEs) have been a serious issue with immunotherapy. By turning off regulatory mechanisms, the immune system can go into overdrive causing issues such as Cytokine Release Syndrome (CRS)—an inflammatory process that can cause high fever and sometimes organ failure ( 18 , 50 , 54 ). This is part of what is sometimes referred to as a “cytokine storm” reaction to a pathogen or in the present discussion, CAR-T or checkpoint inhibition therapy, where a marked dysregulation of cytokine production can lead to fatal outcomes ( 18 ).…”

Section: A Brief History Of Cancer Immunotherapymentioning

confidence: 99%

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

Barchi

2022

Front. Immunol.

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For many years, cell-surface glycans (in particular, Tumor-Associated Carbohydrate Antigens, TACAs) have been the target of both passive and active anticancer immunotherapeutic design. Recent advances in immunotherapy as a treatment for a variety of malignancies has revolutionized anti-tumor treatment regimens. Checkpoint inhibitors, Chimeric Antigen Receptor T-cells, Oncolytic virus therapy, monoclonal antibodies and vaccines have been developed and many approvals have led to remarkable outcomes in a subset of patients. However, many of these therapies are very selective for specific patient populations and hence the search for improved therapeutics and refinement of techniques for delivery are ongoing and fervent research areas. Most of these agents are directed at protein/peptide epitopes, but glycans–based targets are gaining in popularity, and a handful of approved immunotherapies owe their activity to oligosaccharide targets. In addition, nanotechnology and nanoparticle-derived systems can help improve the delivery of these agents to specific organs and cell types based on tumor-selective approaches. This review will first outline some of the historical beginnings of this research area and subsequently concentrate on the last 5 years of work. Based on the progress in therapeutic design, predictions can be made as to what the future holds for increasing the percentage of positive patient outcomes for optimized systems.

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“…In blood tumors, despite the relative specificity of the CD19 receptor, bone marrow aplasia can occur resulting in death or requiring stem cells transplantation [ 29 , 30 ]. Despite the developed treatment in the form of tocilizumab (an anti-IL-6 receptor antibody), there are cases where the patient dies regardless of its application [ 31 , 32 ]. Besides the mentioned tocilizumab, there is also treatment with siltuximab (anti-IL-6 antibody) [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Application and Design of Switches Used in CAR

Głowacki

Rieske

2022

Cells

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Among the many oncology therapies, few have generated as much excitement as CAR-T. The success of CAR therapy would not have been possible without the many discoveries that preceded it, most notably, the Nobel Prize-winning breakthroughs in cellular immunity. However, despite the fact that CAR-T already offers not only hope for development, but measurable results in the treatment of hematological malignancies, CAR-T still cannot be safely applied to solid tumors. The reason for this is, among other things, the lack of tumor-specific antigens which, in therapy, threatens to cause a lethal attack of lymphocytes on healthy cells. In the case of hematological malignancies, dangerous complications such as cytokine release syndrome may occur. Scientists have responded to these clinical challenges with molecular switches. They make it possible to remotely control CAR lymphocytes after they have already been administered to the patient. Moreover, they offer many additional capabilities. For example, they can be used to switch CAR antigenic specificity, create logic gates, or produce local activation under heat or light. They can also be coupled with costimulatory domains, used for the regulation of interleukin secretion, or to prevent CAR exhaustion. More complex modifications will probably require a combination of reprogramming (iPSc) technology with genome editing (CRISPR) and allogenic (off the shelf) CAR-T production.

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A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy

Cited by 30 publications

References 47 publications

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

Application and Design of Switches Used in CAR

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