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1.
Bull Cancer ; 108(12S): S90-S97, 2021 Dec.
Article in French | MEDLINE | ID: covidwho-1559003

ABSTRACT

Infections occurring after CAR T-cells are a common complication. At the acute phase of treatment following CAR T-cell infusion, the exact incidence of infections is unknown given the overlapping symptoms with cytokine release syndrome. The risk factors for infection include the malignant underlying disease and its multiple treatments, and an immunosuppressive state induced by CAR-T cells themselves and the treatment of their complications. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of post-CAR infectious complications. In this review we discuss anti-infection prophylaxis and vaccination of patients undergoing CAR T-cell therapy as well as a special chapter for the specific case of COVID-19. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management and prevention of infectious complications associated with this new therapeutic approach.


Subject(s)
Bacterial Infections/prevention & control , Immunotherapy, Adoptive , Mycoses/prevention & control , Receptors, Chimeric Antigen/therapeutic use , Virus Diseases/prevention & control , Bone Marrow Transplantation , COVID-19/prevention & control , Cell Transplantation , Cytokine Release Syndrome , Humans , Immunization , Immunocompromised Host , Immunoglobulins/therapeutic use , Immunotherapy, Adoptive/adverse effects , Neoplasms/complications , Neoplasms/therapy , Pneumocystis , Risk Factors
2.
Signal Transduct Target Ther ; 6(1): 367, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475287

ABSTRACT

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.


Subject(s)
Cytokine Release Syndrome , Signal Transduction/immunology , Acute Disease , Autoimmune Diseases/complications , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Graft vs Host Disease/complications , Graft vs Host Disease/immunology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive/adverse effects , Influenza, Human/complications , Influenza, Human/immunology , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/therapy
3.
Int J Mol Sci ; 22(14)2021 Jul 17.
Article in English | MEDLINE | ID: covidwho-1323267

ABSTRACT

Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies.


Subject(s)
Cytokine Release Syndrome/etiology , Hematologic Neoplasms/immunology , Hematologic Neoplasms/therapy , Immunotherapy, Adoptive/adverse effects , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Animals , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/therapy , Humans
4.
Blood ; 138(9): 811-814, 2021 09 02.
Article in English | MEDLINE | ID: covidwho-1288619
5.
JCO Clin Cancer Inform ; 5: 668-678, 2021 06.
Article in English | MEDLINE | ID: covidwho-1264197

ABSTRACT

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell-associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments-based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T-related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.


Subject(s)
Cytokine Release Syndrome/etiology , Immunotherapy, Adoptive/adverse effects , Telemedicine/methods , COVID-19 , Cell- and Tissue-Based Therapy/adverse effects , Humans , Immunotherapy, Adoptive/methods , Machine Learning , Neurotoxicity Syndromes/etiology , Precision Medicine , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen
6.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1261212

ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.


Subject(s)
Ambulatory Care , Antigens, CD19/immunology , Immunotherapy, Adoptive , Lymphoma, B-Cell/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Chimeric Antigen/genetics , T-Lymphocytes/transplantation , Ambulatory Care/economics , Cost-Benefit Analysis , Hospital Costs , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/economics , Immunotherapy, Adoptive/mortality , Lymphoma, B-Cell/economics , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/mortality , Patient Safety , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Risk Assessment , Risk Factors , T-Lymphocytes/immunology , Treatment Outcome
7.
Blood Rev ; 45: 100707, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064893

ABSTRACT

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.


Subject(s)
COVID-19/immunology , Castleman Disease/immunology , Cytokine Release Syndrome/immunology , Immunologic Factors/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , SARS-CoV-2/pathogenicity , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Biomarkers/blood , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Castleman Disease/drug therapy , Castleman Disease/pathology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Ferritins/blood , Ferritins/immunology , Gene Expression Regulation , Humans , Immunotherapy, Adoptive/adverse effects , Interleukin-1/antagonists & inhibitors , Interleukin-1/blood , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Interleukin-6/immunology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/pathology , Signal Transduction
8.
Am J Emerg Med ; 48: 357-360, 2021 10.
Article in English | MEDLINE | ID: covidwho-1051416

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronavirus family, which causes coronavirus disease 2019 (COVID-19). The phenotype of the disease varies from asymptomatic, to a mild phenotype, through to the severe form of acute respiratory distress syndrome (ARDS), which often leads to death, especially in those with underlying diseases. It has been reported that those who suffer from cancer (especially lung cancer and hematological malignancies) are at higher risk of serious complications and death from COVID-19. Some cancer treatments such as CAR T cell therapy can produce a cytokine storm, which is also a hallmark of severe COVID-19. Therefore, patients receiving CAR T cells are at higher risk if they become infected with COVID-19, and could be treated with anti-cytokine approaches.


Subject(s)
COVID-19/physiopathology , Neoplasms/physiopathology , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/immunology , Disease Susceptibility , Hematologic Neoplasms/complications , Hematologic Neoplasms/immunology , Hematologic Neoplasms/physiopathology , Hematologic Neoplasms/therapy , Humans , Immunocompromised Host , Immunotherapy, Adoptive/adverse effects , Lung Neoplasms/complications , Lung Neoplasms/immunology , Lung Neoplasms/physiopathology , Lung Neoplasms/therapy , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , Receptors, Chimeric Antigen , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology
9.
Bone Marrow Transplant ; 56(3): 570-580, 2021 03.
Article in English | MEDLINE | ID: covidwho-779977

ABSTRACT

An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. This retrospective study evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by severe COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Grade 4 CRS was significantly more common in the COVID-19 group (15/40 (35.7%) vs. 5/41 (12.2%), P = 0.008). The CAR-T group had more dramatic increase in cytokines, including IL-2, IL-6, IL-10, and IFN-γ. Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml (16.1-70.0) vs. 3.3 (1.8-9.6), P < 0.001) and lg viral loads were correlated with lg IL-6 (R2 = 0.101; P < 0.001) and lg IL-10 (R2 = 0.105; P < 0.001). The independent risk factor for COVID-19-related sCRS was hypertension history (OR: 4.876, 95% CI: 2.038-11.668; P < 0.001). Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of severe COVID-19-related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.


Subject(s)
COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/etiology , Immunotherapy, Adoptive/adverse effects , Receptors, Chimeric Antigen/immunology , SARS-CoV-2 , Adult , Aged , C-Reactive Protein/metabolism , COVID-19/epidemiology , China/epidemiology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokines/blood , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Lung/diagnostic imaging , Male , Middle Aged , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , Pandemics , Procalcitonin/blood , Prognosis , Retrospective Studies , Risk Factors , Tumor Burden/immunology , Viral Load/immunology
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