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Grading and management of CRS. Considerations and approaches for the grading and management of CRS. The symptoms are divided into grade 1 to grade 4 according to the ASBMT consensus grading. 83 Tocilizumab: a maximum of 800 mg per dose is recommended; a maximum of 3 doses in 24 hours are recommended. Low-dose corticosteroids: ie, 10 mg dexamethasone every 6 hours or equivalent. High-dose corticosteroids: 1000 mg methylprednisolone every 24 hours or equivalent. CRS = cytokine release syndrome. ASBMT = American Society for Blood and Marrow Transplantation.
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The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as “i...
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... tocilizumab was just given once and half of the recommended dose. 82 Figure 2 shows a grading-guided approach for the management of CRS. ...
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... Prolonged cytopenia was experienced by 43% of patients. A total of 28 deaths (2%) occurred (Table 4) [68,69]. ...
Acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR’s high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs.
... Alternatively, the American Society for Transplantation and Cellular Therapy (ASTCT) expert panel has recently coined the term "immune effector cell-associated HLH-like syndrome" (IEC-HS) to describe this phenomenon with the objective of unifying prior definitions. Recognition of IEC-HS as a biochemically and genetically distinct disorder from other previously described HLH syndromes facilitates further exploration of its distinct etiology and mechanistic features [29]. Management of this entity is of vital importance to avoid poor outcomes, but diagnosis can be difficult due to overlapping clinical presentation with other CAR-T toxicities like CRS and progressive leukemia/lymphoma. ...
Simple Summary
Chimeric antigen receptor (CAR)-T cells are a novel type of therapy that is becoming more prominent in the treatment of many hematological malignancies. They are associated with serious side effects including hemophagocytic lymphohistiocytosis (HLH), which can be fatal. Diagnosis of HLH can be challenging due to the lack of a uniform diagnostic criteria and the overlap with other frequent toxicities of CAR-T cells. Available treatments have been previously used for HLH but may not be as effective in this setting. The purpose of this literature review was to examine the evolution of the diagnostic criteria and treatment recommendations for HLH specifically in the setting of CAR-T cell therapy in order to facilitate prompt diagnosis and the implementation of suitable treatment to improve patient outcomes.
Abstract
Since CAR-T cell therapy was initially approved in 2017, its use has become more prevalent and so have its side effects. CAR-T-related HLH, also named immune effector cell-associated HLH-like syndrome (IEC-HS), is a rare but fatal toxicity if not recognized promptly. We conducted a review of the literature in order to understand the prevalence of IEC-HS as well as clarify the evolution of the diagnostic criteria and treatment recommendations. IEC-HS occurrence varies between CAR-T cell products and the type of malignancy treated. Diagnosis can be challenging as there are no standardized diagnostic criteria, and its clinical features can overlap with cytokine release syndrome and active hematological disease. Suggested treatment strategies have been extrapolated from prior experience in HLH and include anakinra, corticosteroids and ruxolitinib. IEC-HS is a potentially fatal toxicity associated with CAR-T cell therapy. Early recognition with reliable diagnostic criteria and prompt implementation of treatment specific to IEC-HS is imperative for improving patient outcomes.
... Antipyretics and fluids are used as symptomatic treatments for low-grade CRS. Given the possibility of vascular leakage and subsequent pulmonary edema, caution should be given when replacing large amounts of intravenous fluid (286). The mainstay of CRS therapy has been the selective blockade of IL-6 signaling by tocilizumab (IL-6 receptor antagonist) or siltuximab (chimeric anti-IL-6 mAb), which results in rapid resolution of CRS symptoms, usually within a few hours. ...
... Similar to how CRS is managed, patients with mild (grade ≤1) neurotoxicity should be continuously evaluated and given supportive treatment as necessary. Transfer to an intensive care unit or intermediate care unit should be considered for individuals who experience more severe neurotoxicity (grade≥2) (286). The identification of additional causes of neurological symptoms, such as cerebral hemorrhage, CNS involvement of the underlying malignancy, stroke, infection, and others, requires consultation with a neurologist or neurointensivist as well as a lumbar puncture and radiological imaging (297). ...
... As a suggested therapy, 10 mg of dexamethasone should be taken every six hours until the symptoms go away. While, high doses of methylprednisolone (such as 1000 mg/24h) should be administered in cases with grade-4 toxicity (286). ...
The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.
... In the studies conducted, it has been stated that in patients with COVID-19, a rapid deterioration of the clinical picture can be observed especially within the second week of the disease. This hyper-inflammation is usually manifested by an unexpected aggravation of symptoms such as high fever and respiratory distress and is associated with an increase in acute phase reactants (erythrocyte sedimentation rate (ESR), CRP, and ferritin), coagulation factors (D-dimer), and intracellular lysis markers (lactate dehydrogenase (LDH), creatine kinase (CK)) [2,4,26,27]. Increased cytokine levels observed in the COVID-19-related cytokine storm, unlike other pneumonitis species, leads to the development of organ dysfunction and the need for intensive care [28]. ...
... Although, not specific for COVID-19-related cytokine storms, it is considered that anti-inflammatory treatment approaches may be useful. It was thought that blocking the overproduction of IL-6, which plays a key role especially in the cytokine storm, could be beneficial in the COVID-19-related cytokine storm [9,12,26,27]. In studies evaluating the effects of TCZ treatment on clinical improvement, the need for mechanical ventilation, and survival in severe COVID-19 cases with cytokine storm conflicting results have been reported [10,31,32]. ...
Objective: In coronavirus disease – 19 (COVID-19) patients, cytokine storm develops due to the increase of pro-inflammatory cytokines. Tocilizumab (TCZ), has been used in the treatment of COVID-19 patients and successful results have been obtained. The aim of this study was to determine the efficacy of TCZ and also investigate the prognostic factors affecting the success of treatment and mortality in COVID-19 patients treated with TCZ. Patients and Methods: Between March 2020 and August 2021, a total of 326 confirmed severe COVID-19 pneumonia patients, treated in the intensive care unit, were included in the study. Results: The mean age of the patients was 63.02±11.58 years, and 203 (62.3%) of the patients were male. Patients treated with TCZ therapy had a longer survival time compared with the standard therapy (p=0.012). It was found that type of respiratory support (HR:2.19, CI:1.10-4.36, p=0.025) and hyperlactatemia on the day of TCZ therapy admission (HR:2.93 CI:1.53-5.64, p=0.001) were the significant and independent prognostic factors of survival in severe COVID-19 pneumonia patients treated with TCZ. Conclusion: Tocilizumab therapy improved 30-days survival in critically ill COVID-19 pneumonia patients. Also, among the patients treated with TCZ, types of respiratory support and hyperlactatemia on the day of TCZ admission were the independent prognostic factors.
... Cytokine release syndrome was only considered in the context of chimeric antigen receptor (CAR) T-cell therapy [26]. ...
The significance of extreme hyperferritinemia and its association with certain diagnoses and prognoses are not well characterized. We performed a retrospective analysis of adult patients with at least one total serum ferritin (TSF) measurement ≥ 5000 µg/L over 2 years, in three university hospitals. Conditions associated with hyperferritinemia were collected, and patients were classified into 10 etiological groups. Intensive care unit (ICU) transfer and mortality rates were recorded. A total of 495 patients were identified, of which 56% had a TSF level between 5000 and 10,000 µg/L. There were multiple underlying causes in 81% of the patients. The most common causes were infections (38%), hemophagocytic lymphohistiocytosis (HLH, 18%), and acute hepatitis (14%). For TSF levels > 10,000 µg/L, there were no solid cancer or hematological malignancy without another cause of hyperferritinemia. Isolated iron-overload syndromes never exceeded TSF levels > 15,000 µg/L. Extreme hyperferritinemia (TSF levels > 25,000 µg/L) was associated with only four causes: HLH, infections, acute hepatitis and cytokine release syndromes. A total of 32% of patients were transferred to an ICU, and 28% died. Both ICU transfer rate and mortality were statistically associated with ferritin levels. An optimized threshold of 13,405 μg/L was the best predictor for the diagnosis of HLH, with a sensitivity of 76.4% and a specificity of 79.3%. Hyperferritinemia reflects a variety of conditions, but only four causes are associated with extreme hyperferritinemia, in which HLH and acute hepatitis are the most common. Extreme hyperferritinemia has a poor prognosis with increased mortality.
... ICANS is one of the most common CAR T cell therapy-related toxicities associated with CRS. Data from multiple clinical trials data indicate that ICANS may be associated with the CAR construct and the antigen targeted by CAR T cells also, and the severity of ICANS can be correlated with the severity of CRS, higher tumor burden, a higher dose of CAR T cells, and their higher in vivo expansion rates (Turtle et al., 2017;Brudno et al., 2018;Gauthier and Turtle, 2018;Park et al., 2018;Santomasso et al., 2018;Garcia Borrega et al., 2019). It has been observed in the ZUMA-1 CAR T cells trial that the onset of ICANS occurs later than CRS and that symptoms persist longer than CRS symptoms (Santomasso et al., 2018). ...
... It has been observed in the ZUMA-1 CAR T cells trial that the onset of ICANS occurs later than CRS and that symptoms persist longer than CRS symptoms (Santomasso et al., 2018). Symptoms of ICANS range from mild headaches, fatigue, and mild aphasia to severe manifestation in the form of seizures, raised intracranial pressure with cerebral edema, and coma (Santomasso et al., 2018;Garcia Borrega et al., 2019). ...
... Preclinical studies indicated that blockade of IL-1 and GM-CSF by anakinra and lenzilumab can be an approach toward the management of ICANS. However, it should be noted that IL-6 blockade by tocilizumab used in case CRS is not effective in case of ICANS (Shimabukuro-Vornhagen et al., 2018a;Norelli et al., 2018;Garcia Borrega et al., 2019;Yáñez et al., 2019). Table 4 provides details of common toxicities associated with CAR T cell therapies as observed in major clinical studies. ...
Ex vivo expansion of T lymphocytes is a central process in the generation of cellular therapies targeted at tumors and other disease-relevant structures, which currently cannot be reached by established pharmaceuticals. The influence of culture conditions on T cell functions is, however, incompletely understood. In clinical applications of ex vivo expanded T cells, so far, a relatively classical standard cell culture methodology has been established. The expanded cells have been characterized in both preclinical models and clinical studies mainly using a therapeutic endpoint, for example antitumor response and cytotoxic function against cellular targets, whereas the influence of manipulations of T cells ex vivo including transduction and culture expansion has been studied to a much lesser detail, or in many contexts remains unknown. This includes the circulation behavior of expanded T cells after intravenous application, their intracellular metabolism and signal transduction, and their cytoskeletal (re)organization or their adhesion, migration, and subsequent intra-tissue differentiation. This review aims to provide an overview of established T cell expansion methodologies and address unanswered questions relating in vivo interaction of ex vivo expanded T cells for cellular therapy.
... Lowgrade CRS can be treated symptomatically (antipyretics and fluids), whereas patients developing CRS of grade 3 or 4 may be treated with vasopressors, tocilizumab (antiinterleukin (IL)-6 receptor antagonist), and/or low-dose, or if required, high-dose corticosteroids. 13 Neurotoxicity, also known as immune effector cellassociated neurotoxicity syndrome (ICANS), has been reported in all CD19 CAR T clinical trials exhibiting a robust immune response, 14 with more than 60% of patients experiencing toxic neurological effects (figure 1). While neurotoxicity has often been described to be associated Figure 1 Overview of the main adverse events associated with engineered T cells. ...
Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.
... Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are immune-mediated toxicities characterized by overexpression and hyper-activation of pro-inflammatory cytokines, within which TNF-α plays a key pathogenetic role [24][25][26]. ...
Early post-transplant is the critical phase for the success of hematopoietic stem cell transplantation (HSCT). New viral infections and the reactivations associated with complete ablation of the recipient’s T-cell immunity and inefficient reconstitution of the donor-derived system represent the main risks of HSCT. To date, the pharmacological treatments for post-HSCT viral infection-related complications have many limitations. Adoptive cell therapy (ACT) represents a new pharmacological strategy, allowing us to reconstitute the immune response to infectious agents in the post-HSC period. To demonstrate the potential advantage of this novel immunotherapy strategy, we report three cases of pediatric patients and the respective central nervous system complications after donor lymphocyte infusion.
... Symptoms and Management of ICANS grades[119]. ...
... 42,43 Although the mechanisms contributing these inflammatory toxicities are not completely understood, previous studies have suggested that inflammatory cytokines produced by CAR-T cells contribute to these systemic inflammatory toxicities in part by activating bystander myeloid cells. 42,[44][45][46][47] T-cell-derived proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ have been suggested to play a role in activating these bystander myeloid cells, 44,48 thus, various strategies to modulate expression of these cytokines have been proposed to improve the safety of CAR-T cells. 44,45,49 To assess if TCR I has any effect on inflammatory cytokine production by CAR-T cells, CD19 CAR-T cells were manufactured following TCR I or TCR D . ...
... CAR-T therapy is also associated with systemic inflammatory toxicities, known as CRS, along with neurotoxicity. 48,54,55 During these inflammatory toxicities, cytokines such as GM-CSF and IFN-γ are released at high levels. 48,56 These inflammatory cytokines, released by activated CAR-T cells, in turn activate bystander immune cells such as monocytes and macrophages, which then produce IL-6, IL-1β, etc., and contributes to a cascading response of CRS and neurotoxicity. ...
... 48,54,55 During these inflammatory toxicities, cytokines such as GM-CSF and IFN-γ are released at high levels. 48,56 These inflammatory cytokines, released by activated CAR-T cells, in turn activate bystander immune cells such as monocytes and macrophages, which then produce IL-6, IL-1β, etc., and contributes to a cascading response of CRS and neurotoxicity. 46,47,54 It is interesting to note that we found that CAR-T cells manufactured following TCR I activation produced significantly less GM-CSF and IFN-γ following co-culture with target cells compared with CAR-T cells manufactured via TCR D activation. ...
Chimeric antigen receptor expressing T cells (CAR-T cells) have shown remarkable efficacy against some blood cancers and have potential to treat many other human diseases. During CAR-T cell manufacturing, T cells are activated via engagement of the T-cell receptor (TCR); however, persistent TCR engagement can induce unchecked activation, differentiation, and exhaustion, which can negatively affect CAR-T cell product quality and in vivo potency. In addition, T cells may not uniformly respond to TCR-dependent activation (TCRD) contributing to lot-to-lot variability, poor expansion, and manufacturing failures. TCRD also presents challenges during manufacturing of allogeneic CAR-T cells when endogenous TCR is deleted to prevent graft-versus-host disease. Thus, novel strategies to activate T cells may help improve CAR-T cell product attributes and reduce manufacturing failures. In this study, we compared the effect of TCRD and TCR-independent activation (TCRI) on CAR-T cell product attributes. We found that TCRI in presence of a Src-kinase inhibitor significantly improved CAR-T cell expansion and yield without affecting viability and CD4/CD8 ratio. Markers of T-cell activation, exhaustion and differentiation were also reduced in these CAR-T cells compared with CAR-T cells manufactured by TCRD. TCRI did not affect CAR-T cell in vitro potency; however, following co-culture with target cells, CAR-T cells manufactured by TCRI released significantly less inflammatory cytokines compared with CAR-T cells manufactured by TCRD. Together, these data suggest that manufacturing CAR-T cells by TCRI activation in the presence of a Src-kinase inhibitor improves product quality attributes and may help reduce manufacturing failures and improve CAR-T cell safety and efficacy in vivo.
