Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice

Bonaldo, Giulia; AlbertoVaccheri,; Motola, Domenico

doi:10.1007/s00228-021-03106-z

Cited by 8 publications

(9 citation statements)

References 25 publications

(27 reference statements)

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“…The demographics of the CAR-T-cell reports were in line with previous pharmacovigilance studies [16,24,25]. More reports from male patients were expected (channeling bias), as both DLBCL and ALL show a higher prevalence in male patients, as reported by the US cancer scientific authority [26,27].…”

Section: Case Demographicssupporting

confidence: 73%

“…In Europe, an accelerated assessment application through the Priority Medicines (PRIME) scheme for orphan diseases has been granted for CAR-T cells and additional monitoring and post-authorization safety studies have been required by the European Medicines Agency [12] after marketing authorization. Increasing post-marketing data have been recorded for CAR-T-cell safety profile monitoring in a real-world setting, where a significantly larger and heterogeneous population of patients has been treated [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Fusaroli

Isgrò

Cutroneo³

et al. 2022

Drug Saf

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Introduction As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. MethodsWe queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1). Conclusions Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.

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Section: Case Demographicssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Fusaroli

Isgrò

Cutroneo³

et al. 2022

Drug Saf

View full text Add to dashboard Cite

show abstract

“…Although about 20% of the reports did not have the patients’ sex available, the authors did not find a significant difference between male and female patients. 163 However, as the indications and use of these therapies expand to a wider group of patients, future studies should especially focus on the potential sex differences not only in efficacy, but also in short- and long-term immune-based toxicities, including cardiovascular ones.…”

Section: Immunotherapymentioning

confidence: 99%

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

Wilcox

Rotz

Mullen

et al. 2022

Circulation Research

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In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies.

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“…However, there are many side effects and complications associated with these conventional antitumor treatment methods . In recent years, immunotherapy has been the major therapeutic strategy in cancer treatment. − Three main cancer immunotherapies have been developed to improve the therapeutic efficiency: cancer vaccines, , chimeric antigen receptor T-cell (CAR-T) therapies, , and immune checkpoint therapies. − As an effective immunotherapy strategy, in a tumor microenvironment, the immune checkpoint blockade treatment is intended to enhance the function of T-cells by blocking the inhibitory receptors of T-cells. Currently, the development of mAbs to block programmed death-1 receptor (PD-1)/programmed death-ligand 1 (PD-L1) has made substantial advances.…”

Section: Introductionmentioning

confidence: 99%

“…1 In recent years, immunotherapy has been the major therapeutic strategy in cancer treatment. 2−4 Three main cancer immunotherapies have been developed to improve the therapeutic efficiency: cancer vaccines, 5,6 chimeric antigen receptor T-cell (CAR-T) therapies, 7,8 and immune checkpoint therapies. 9−11 As an effective immunotherapy strategy, in a tumor microenvironment, the immune checkpoint blockade treatment is intended to enhance the function of T-cells by blocking the inhibitory receptors of T-cells.…”

Section: ■ Introductionmentioning

confidence: 99%

NIR-II Fluorescent Molecular Bottlebrush Prepared by Ring-Opening Polymerization for Programmed Cell Death Ligand-1 Checkpoint Imaging

Wang

Sun

Fan

et al. 2021

ACS Appl. Polym. Mater.

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In the area of tumor therapy, the immune checkpoint drugs programmed death-1 receptor (PD-1) and programmed death-ligand 1 (PD-L1) have been widely used in clinical trials and shown excellent therapeutic effects. The PD-L1 expression on cancer cells can be considered the predictive biomarker for patients, and the second near-infrared (NIR-II) window fluorescence imaging is ideal for immune checkpoint research. Conjugated polymers, as a kind of organic semiconductor, have very extensively applications in NIR-II fluorescence imaging, but the biological application is limited with the poor water solubility. Here, we developed a brush-on-brush molecular bottlebrush through a two-step "grafting from" strategy by ring-opening polymerization (ROP). Then, a PD-L1 monoclonal antibody (mAb) was conjugated with a molecular bottlebrush to afford the fluorophore (anti-PD-L1)-P(TTQ-F)-g-(PLL 30 -g-(PGA) 5 ) specific to the PD-L1 checkpoint. The fluorophore exhibits strong NIR-II fluorescence signals and selective targeting ability of PD-L1. Moreover, after an intravenous injection of (anti-PD-L1)-P(TTQ-F)-g-(PLL 30 -g-(PGA) 5 ) into the BALB/c mice bearing CT26 tumors, the tumor-to-normal tissue (T/NT) signal ratio sharply increased with a maximum T/NT = 11.90 at 12 h p.i. during the initial 12 h post-injection. This study provides bright future outlooks for immune checkpoint imaging and further immunotherapy.

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Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice

Cited by 8 publications

References 25 publications

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

NIR-II Fluorescent Molecular Bottlebrush Prepared by Ring-Opening Polymerization for Programmed Cell Death Ligand-1 Checkpoint Imaging

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