Macrophage, the potential key mediator in CAR-T related CRS.
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ABSTRACT:
SUBMITTER: Hao Z
PROVIDER: S-EPMC7349474 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.
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Project description:CAR-T cell therapy has demonstrated efficacy in treating certain hematological malignancies. However, the administration of CAR-T cells is accompanied by the occurrence of adverse events. Among these, cytokine release syndrome (CRS) has garnered significant attention. In this descriptive study, we set the search criteria to retrieve and obtain articles regarding CAR-T cell-related CRS from the Web of Science Core Collection (WoSCC). The bibliometric and knowledge-map analysis of these documents was conducted using Microsoft Excel 2019, GraphPad Prism 8, CtieSpace, and VOSviewer. 6,623 authors from 295 institutions in 49 countries coauthored a total of 1,001 publications. The leading country in this field was the United States. The most productive institution was the University of Pennsylvania. Carl H. June had the most citations, while Daniel W. Lee had the most co-citations. Research hotspots primarily concentrated on the pathogenesis, serum biomarkers, management, and therapeutic drugs of CRS, alongside neurotoxicity. Emerging topics within this discipline encompassed the following: a. Drugs for effective treatment and intervention of CRS; b. Conducting pertinent clinical trials to acquire real-world data; c. Management of toxicity (CRS and neurotoxicity) associated with CAR-T cell therapy; d. The study of BCMA-CAR-T cells in multiple myeloma (MM); e. Optimizing the CAR framework structure to enhance the effectiveness and safety of CAR-T cells. A bibliometric and scientific knowledge-map analysis provided a unique and objective perspective for exploring the field of CAR-T cell-related CRS, and may provide some new clues and valuable references for researchers.
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Project description:Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1β (IL1β) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1β signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1β with adalimumab and anti-IL1β antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1β antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1β blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.
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Project description:The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly because of the expanding indications for standard-of-care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential in facilitating the widespread use. Preemptive interventions to prevent more severe toxicities have improved safety, facilitating CAR T-cell therapy in medically frail populations and in those at high risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic because it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.
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Project description:Treatment with CD19 or CD22-targeted chimeric antigen receptor-engineered T (CD19/CD22 CAR-T) cells achieve complete responses in 60-90% of adults and children with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL). This led to the approval of tisagenlecleucel (Kymriah) by the FDA and several European regulatory agencies in ALL patients up to 25 years of age. Although CAR T-cell therapy is likely to transform the ALL therapeutic landscape, its development and wide dissemination have been impacted by the occurrence of significant toxicities; namely, cytokine release syndrome (CRS) and Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) have been reported at higher rates in ALL patients compared to other B cell malignancies, particularly in the adult population. Here, we review recent data suggesting a significant proportion of ALL patients are at risk of developing severe, sometimes life-threatening, CRS, and ICANS after CD19 and CD22 CAR T-cell therapy. After describing the key clinical and laboratory features of severe CRS and ICANS, we explore the disease and treatment-related factors that may predict the severity of these toxicities. Last, we review strategies under investigation in the prophylactic and therapeutic settings to improve the safety of CAR T-cells for ALL.
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Project description:Adoptive cell therapy with chimeric antigen receptor (CAR) immunotherapy has made tremendous progress with five CAR T therapies approved by the US Food and Drug Administration for hematological malignancies. However, CAR immunotherapy in solid tumors lags significantly behind. Some of the major hurdles for CAR immunotherapy in solid tumors include CAR T cell manufacturing, lack of tumor-specific antigens, inefficient CAR T cell trafficking and infiltration into tumor sites, immunosuppressive tumor microenvironment (TME), therapy-associated toxicity, and antigen escape. CAR Natural Killer (NK) cells have several advantages over CAR T cells as the NK cells can be manufactured from pre-existing cell lines or allogeneic NK cells with unmatched major histocompatibility complex (MHC); can kill cancer cells through both CAR-dependent and CAR-independent pathways; and have less toxicity, especially cytokine-release syndrome and neurotoxicity. At least one clinical trial showed the efficacy and tolerability of CAR NK cell therapy. Macrophages can efficiently infiltrate into tumors, are major immune regulators and abundantly present in TME. The immunosuppressive M2 macrophages are at least as efficient as the proinflammatory M1 macrophages in phagocytosis of target cells; and M2 macrophages can be induced to differentiate to the M1 phenotype. Consequently, there is significant interest in developing CAR macrophages for cancer immunotherapy to overcome some major hurdles associated with CAR T/NK therapy, especially in solid tumors. Nevertheless, both CAR NK and CAR macrophages have their own limitations. This comprehensive review article will discuss the current status and the major hurdles associated with CAR T and CAR NK therapy, followed by the structure and cutting-edge research of developing CAR macrophages as cancer-specific phagocytes, antigen presenters, immunostimulators, and TME modifiers.
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Project description:BackgroundChimeric antigen receptor T-cell (CAR-T) therapy is a new and efficient cellular immunotherapy. The therapy shows significant efficacy, but also has serious side effects, collectively known as cytokine release syndrome (CRS). At present, some CRS-related cytokines and their roles in CAR-T therapy have been confirmed by experimental studies. However, the mechanism of CRS remains to be fully understood.MethodsBased on big data for human protein interactions and meta-learning graph neural network, we employed known CRS-related cytokines to comprehensively investigate the CRS associated cytokines in CAR-T therapy through protein interactions. Subsequently, the clinical data for 119 patients who received CAR-T therapy were examined to validate our prediction results. Finally, we systematically explored the roles of the predicted cytokines in CRS occurrence by protein interaction network analysis, functional enrichment analysis, and pathway crosstalk analysis.ResultsWe identified some novel cytokines that would play important roles in biological process of CRS, and investigated the biological mechanism of CRS from the perspective of functional analysis.Conclusions128 cytokines and related molecules had been found to be closely related to CRS in CAR-T therapy, where several important ones such as IL6, IFN-γ, TNF-α, ICAM-1, VCAM-1 and VEGFA were highlighted, which can be the key factors to predict CRS.
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