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Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Post-transplant or hematological cancer patients have a higher risk of mortality after infection with ancestral and early variants of severe acute respiratory syndrome (SARS)-CoV-2. Adoptive cell therapy (ACT) with virus-specific T cells (VSTs) could augment endogenous T cell immunity to avoid disease deterioration before viral clearance. We established a third-party SARS-CoV-2-specific T cell (COVID-T) bank in 2020 (NCT04351659) using convalescent and/or vaccinated donors. In a phase I/II study (NCT04457726), 13 adult and pediatric patients, acutely positive for SARS-CoV-2 and predicted to have a high chance of mortality, were recruited from September 2021 to February 2022. Twelve patients received a single dose of COVID-T cells, matched on at least 1 HLA. A dose of either 75,000 or 150,000 IFN-γ+CD3+ cells/m2 SARS-COV-2-specific T cells did not cause cytokine release syndrome, acute respiratory distress syndrome, or graft-versus-host disease. In the 8 patients who had detectable donor SARS-COV-2-specific T cells after ACT, none progressed to severe disease or died with COVID-19. In contrast, among the other four patients without evidence of donor micro-chimerism, two died of COVID-19. Long-acting third-party VSTs from convalescent or vaccinated donors could be expediently produced and might be clinically useful in future pandemics, particularly before global vaccination is implemented. [ABSTRACT FROM AUTHOR]

In severe COVID-19 cases, an exacerbated inflammatory response triggers a cytokine storm that can worsen the prognosis. Compounds with both antiviral and anti-inflammatory activities show promise as candidates for COVID-19 therapy, as they potentially act against the SARS-CoV-2 infection regardless of the disease stage. One of the most attractive drug targets among coronaviruses is the main protease (MPro). This enzyme is crucial for cleaving polyproteins into non-structural proteins required for viral replication. The aim of this review was to identify SARS-CoV-2 MPro inhibitors with both antiviral and anti-inflammatory properties. The interactions of the compounds within the SARS-CoV-2 MPro binding site were analyzed through molecular docking when data from crystallographic structures were unavailable. 18 compounds were selected and classified into five different superclasses. Five of them exhibit high potency against MPro: GC-376, baicalein, naringenin, heparin, and carmofur, with IC50 values below 0.2 μM. The MPro inhibitors selected have the potential to alleviate lung edema and decrease cytokine release. These molecules mainly target three critical inflammatory pathways: NF-κB, JAK/STAT, and MAPK, all previously associated with COVID-19 pathogenesis. The structures of the compounds occupy the S1/S2 substrate binding subsite of the MPro. They interact with residues from the catalytic dyad (His41 and Cys145) and/or with the oxyanion hole (Gly143, Ser144, and Cys145), which are pivotal for substrate recognition. The MPro SARS-CoV-2 inhibitors with potential anti-inflammatory activities present here could be optimized for maximum efficacy and safety and be explored as potential treatment of both mild and severe COVID-19. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic condition caused by an inflammation mediated mainly by cytokines and T cells. In COVID-19, the same type of imbalance is common, generating the Cytokine Storm and promoting a worsening in the skin conditions of patients with autoimmune disorders, such as Psoriasis. In this context, one of the main mediators of immune responses presented by SARS-CoV-2 infected patients is the Purinergic System. This immunological resource is capable of stimulating the hyperinflammatory state presented by infected individuals, mainly by the activity of the P2X7 receptor, culminating in the Cytokine Storm and consequently in the Psoriasis crisis. Currently, different drugs are used for patients with Psoriasis, such as immunosuppressants and small molecules; however, the safety of these drugs in infected patients has not been analyzed yet. In this context, studies are being developed to evaluate the possible administration of these traditional drugs to COVID-19 patients with Psoriasis crisis. Along with that, researchers must evaluate the potential of administrating P2X7 antagonists to these patients as well, improving both the systemic and the dermatological prognostics of patients, by reducing the Cytokine Storm and its general effects, but also avoiding the provocation of Psoriasis crisis. [ABSTRACT FROM AUTHOR]

Background: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. Methods: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). Results: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. Conclusion: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740). [ABSTRACT FROM AUTHOR]

Introduction: Cytokine release syndrome (CRS) is one of the leading causes of mortality in patients with COVID-19 caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague. Methods: Using spike protein combined with IL-2, IFN-γ, and TNF-α to stimulate human peripheral blood mononuclear cells (PBMCs) to secrete CRS-related cytokines, the content of cytokines in the supernatant was detected, and the effects of NK, T, and monocytes were analyzed. Results: This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more interleukin-2 (IL-2,) which subsequently cooperates with spike protein to facilitate PBMCs to release IL-1β, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as T cells to release IFN-γ Mechanistically, IFN-γ and TNF-α enhance the transcription of CD40, and the interaction of CD40 and its ligand stabilizes the membrane expression of toll-like receptor 4 (TLR4) that serves as a receptor of spike protein on the surface of monocytes. As a result, there is a constant interaction between spike protein and TLR4, leading to continuous activation of nuclear factor-κ-gene binding (NF-κB). Furthermore, TNF-α also activates NF-κB signaling in monocytes, which further cooperates with IFN-γ and spike protein to modulate NF-κB-dependent transcription of CRS-related inflammatory cytokines. Discussion: Targeting TNF-α/IFN-γ in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Osteoporosis, a systemic skeletal disease, is characterized by a quantitative and qualitative, and progressive decrease in bone mass, which is related to inflammation. Since a cytokine storm is triggered in Coronavirus disease 2019 (COVID-19), this study aims to evaluate pro-inflammatory cytokines (TNF-α, IL-1β), Receptor activator of nuclear factor-κB ligand (RANKL)/serum osteoprotegerin (OPG) ratio, and their relationship in mild and severe COVID-19. Methods: This study was performed on 48 adult patients (18 mild, 18 severe COVID-19, and 12 healthy subjects as a control group). Serum OPG, RANKL, TNF-α, IL-1β, 25-OH vitamin D, and ALKp were measured by ELISA and colorimetric assay. Results: COVID-19 patients had a significant increase in RANKL, and RANKL/OPG in mild and severe form (p < 0.001) while OPG decreased significantly in severe form compared to healthy controls (p < 0.05). Inflammatory cytokines (TNF-α and IL-1β) increased in both groups of patients whereas Alkaline phosphatase (ALKp) increased only in severe patients (p < 0.001). Both groups had 25-OH vitamin D deficiency in comparison to healthy ones (p < 0.001). Pearson's correlation coefficient was performed to determine the relationship between RANKL, OPG, ALKp, and 25-OH vitamin D with TNF-α and IL-1β in mild and severe COVID-19, which was statistically significant. Conclusion: Serum RANKL/OPG ratio was elevated in COVID-19 individuals and is assumed to be a risk factor for BMD reduction and osteoporosis in these patients. Correlations between IL-1β, TNF-α, ALKp, 25-OH vitamin D, OPG, RANKL, and RANKL/OPG ratio offered the potential role of these proinflammatory markers in the mechanism of osteoporosis in COVID-19 patients. Summary: Since cytokine storm, can stimulate osteoclastic activity, favoring bone resorption, in this study, we decided to evaluate its molecular mechanisms in COVID-19. We found an elevation of RANKL/OPG ratio with a positive correlation with inflammatory cytokines in COVID-19 which can be assumed as a risk factor for osteoporosis. [ABSTRACT FROM AUTHOR]

Background: In the context of the cytokine storm the takes place in severe COVID-19 patients, the Interleukin 6 (IL6) pathway emerges as one of the key pathways involved in the pathogenesis of this hyperinflammatory state. The strategy of blocking the inflammatory storm by targeting the IL6 is a promising therapy to mitigate mortality. The use of Tocilizumab was recommended by the World Health Organization (WHO) to treat severe COVID-19 patients. However, the efficacy of Tocilizumab is variable. We hypothesize that the genetic background could be behind the efficacy of Tocilizumab in terms of mortality. Methods: We performed a targeted-next generation sequencing of 287 genes, of which 264 belong to a community panel of ThermoFisher for the study of genetic causes of primary immunodeficiency disorders, and 23 additional genes mostly related to inflammation, not included in the original community panel. This panel was sequenced in an initial cohort of 425 COVID-19 patients, of which 232 were treated with Tocilizumab and standard therapy, and 193 with standard therapy only. Selected genetic variants were genotyped by single base extension in additional 245 patients (95 treated with Tocilizumab and 150 non-treated with Tocilizumab). Appropriate statistical analyses and internal validation, including logistic regression models, with the interaction between Tocilizumab and genetic variants, were applied to assess the impact of these genetic variants in the efficacy of Tocilizumab in terms of mortality. Results: Age (p < 0.001) and cardiovascular disease (p < 0.001) are risk factors for mortality in COVID-19 patients. The presence of GG and TT genotypes at IL10Rβ (rs2834167) and IL1β (rs1143633) genes significantly associates with a reduced risk of mortality in patients treated with Tocilizumab (OR = 0.111; 95%CI = 0.015-0.829; p = 0.010 and OR = 0.378; 95%CI = 0.154-0.924; p = 0.028 respectively). The presence of CC genotype at IL1RN (rs2234679) significantly associates with an increased risk of mortality, but only in patients not treated with Tocilizumab (OR = 3.200; 95%CI = 1.512-6.771; p = 0.002). Exhaustive internal validation using a bootstrap method (B = 500 replicates) validated the accuracy of the predictive models. Conclusion: We developed a series of predictive models based on three genotypes in genes with a strong implication in the etiopathogenesis of COVID-19 disease capable of predicting the risk of mortality in patients treated with Tocilizumab. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID19) can cause gastrointestinal complications as well as respiratory tract disease. Coagulation abnormalities and thrombosis frequently occur in COVID19, especially in cases with severe clinical outcome. The relationship between gastrointestinal perforation and coagulopathy due to COVID19 remains unclear. Case presentation: A 49-year-old female received Chimeric antigen receptor T (CAR-T) therapy for an early recurrence of diffuse large B-cell lymphoma (DLBCL) that was refractory to chemotherapy. She was diagnosed with cytokine release syndrome (CRS) because of a fever and oxygen desaturation, and administered tocilizumab. Forty days after completing CAR-T therapy, she was infected with COVID19 and transferred to our hospital. Her general condition worsened and she developed COVID19 pneumonia, and then steroid pulse therapy was started. While her respiratory condition improved, she experienced pain in the anal region and computed tomography (CT) revealed a rectal perforation. An emergency surgery was undertaken, and the lower rectum wall was found to be completely necrotic. Removal of the necrotic part of the rectum tissue, and drainage and lavage of necrotic tissue in the pelvic cavity were performed. The remaining rectum was resected with partial sigmoidectomy, but we could not make the anal stump closed. In addition, an end colostomy in the sigmoid colon was performed. Histopathological findings showed thromboses in the rectal mesentery veins. After the first surgery, the pelvic abscess cavity persisted and her high-grade fever continued. Reoperation was laparoscopically performed, and she underwent a resection of anal canal with residual necrotic rectal and mesorectal tissue, and a drainage of the pelvic abscess. After the reoperation, her general condition improved and CT showed that the abscess cavity had significantly improved. Conclusions: Gastrointestinal perforation, especially rectal necrosis due to coagulopathy caused by severe COVID19 infection, is a rare but life-threatening complication. Physicians should have a high degree of clinical suspicion for timely diagnosis and management, and surgical intervention is necessary in cases of rectal necrosis. [ABSTRACT FROM AUTHOR]

CAR-T cell therapy is a revolutionary new treatment for hematological malignancies, but it can also result in significant adverse effects, with cytokine release syndrome (CRS) being the most common and potentially lifethreatening. The identification of biomarkers to predict the severity of CRS is crucial to ensure the safety and efficacy of CAR-T therapy. To achieve this goal, we characterized the expression profiles of seven cytokines, four conventional biochemical markers, and five hematological markers prior to and following CAR-T cell infusion. Our results revealed that IL-2, IFN-γ, IL-6, and IL-10 are the key cytokines for predicting severe CRS (sCRS). Notably, IL-2 levels rise at an earlier stage of sCRS and have the potential to serve as the most effective cytokine for promptly detecting the condition's onset. Furthermore, combining these cytokine biomarkers with hematological factors such as lymphocyte counts can further enhance their predictive performance. Finally, a predictive tree model including lymphocyte counts, IL-2, and IL-6 achieved an accuracy of 85.11% (95% CI = 0.763-0.916) for early prediction of sCRS. The model was validated in an independent cohort and achieved an accuracy of 74.47% (95% CI = 0.597-0.861). This new prediction model has the potential to become an effective tool for assessing the risk of CRS in clinical practice. [ABSTRACT FROM AUTHOR]

Accurate and rapid quantification of cytokines in biofluids is crucial for early disease diagnosis, management, and prevention. However, it still remains challenging for existing sensors due to the broad dynamic range of cytokines and high interference from sample matrices. To overcome these challenges, electrochemical (EC) and field‐effect transistor (FET) dual‐mode biosensing is integrated on an extended‐gate carbon nanotube field‐effect transistor. This biosensor chip effectively eliminates direct contact between the device and the solution and employs independent signal readouts based on two distinct response mechanisms, thereby circumventing the limitations associated with conventional transistor biosensors. Selective detection of cytokine (e.g., Interferon‐γ, IFN‐γ) is achieved by the FET sensing mode (0.1 to 4000 pg mL−1, with a limit of detection of 24.1 fg mL−1) and the EC sensing mode (0.4–2000 ng mL−1) at different concentration range. The feasibility of real sample analysis using the EC‐FET dual‐mode biosensor is confirmed by detecting salivary levels of IFN‐γ. The combination of EC and FET sensing modes not only provides high sensitivity and a wide response range (seven orders of magnitude) to accommodate various biological samples but also improves the reliability of detection results, which shows promising applications in biological analysis and early disease diagnosis. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Chimeric antigen receptor (CAR) T‐cell therapy is an emerging therapeutic modality for relapsed and refractory hematological malignancies. Infectious complications following CAR T‐cell therapy are not well defined.This is a retrospective analysis of data on patients who received CAR T‐cell therapy between April 2018 and December 2022 at the Karmanos Cancer Center, Detroit. Patients’ data were collected up to their last known clinic or inpatient follow‐up visit. An infectious episode was defined as any microbiologically proven or clinically documented infection.Seventy‐six patients received therapy with FDA‐approved CAR T‐cell products. Thirty‐three patients (43.4%) had at least one infectious episode. There were 61 infectious episodes during a median follow‐up of 184 (96–340) days. Median duration for the onset of infection was 59 (22–209) days. Bacterial and viral infections occurred in 42.6% and 41% of the infectious episodes, respectively. COVID‐19 was the most common infectious complication (14.8%). Time‐to‐event analysis showed that most infections occurred within the first 100 days. Empirical antibiotic use during Cytokine Release Syndrome/Immune effector Cell‐Associated Neurotoxicity Syndrome (CRS/ICANS) in the absence of documented bacterial infection was reported in 85.7% of patients. Clostridioides difficile accounted for 11.5% of all infectious episodes. Five of six patients with C. difficile infection had CRS/ICANS and received antibiotics.COVID‐19 and C. difficile infection were the most common infections following CAR T‐cell therapy. Most infections occurred within the first 100 days. Empiric antibiotic use and C. difficile infection were common in patients with CRS/ICANS, in the absence of documented bacterial infection, thus providing an excellent opportunity for antimicrobial stewardship in this population. [ABSTRACT FROM AUTHOR]

There is a continuous cycle of activation and contraction in the immune response against pathogens and other threats to human health in life. This intrinsic yin-yang of the immune response ensures that inflammatory processes can be appropriately controlled once that threat has been resolved, preventing unnecessary tissue and organ damage. Various factors may contribute to a state of perpetual immune activation, leading to a failure to undergo immune contraction and development of cytokine storm syndromes. A literature review was performed to consider how the trajectory of the immune response in certain individuals leads to cytokine storm, hyperinflammation, and multiorgan damage seen in cytokine storm syndromes. The goal of this review is to evaluate how underlying factors contribute to cytokine storm syndromes, as well as the symptomatology, pathology, and long-term implications of these conditions. Although the recognition of cytokine storm syndromes allows for universal treatment with steroids, this therapy shows limitations for symptom resolution and survival. By identifying cytokine storm syndromes as a continuum of disease, this will allow for a thorough evaluation of disease pathogenesis, consideration of targeted therapies, and eventual restoration of the balance in the yin-yang immune response. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T-cell therapy (CAR-T therapy) has demonstrated significant efficacy in the ZUMA-2 study. After regulatory approvals, several clinical trials and real-world studies on CAR-T therapy for relapsed or refractory mantle cell lymphoma (R/R MCL) were conducted. However, data on clinical safety and efficacy are inconsistent. In this study, we aimed to conduct a systematic analysis of the effectiveness and safety of CAR-T therapy across a wider and more representative cohort of patients with R/R MCL. Methods: We performed a systematic review and meta-analysis of studies on patients with R/R MCL who received CAR-T cell therapy. Data were extracted and consolidated, with primary focus on the evaluation of safety and efficacy outcome measures. This study has not been registered with PROSPERO. Results: This meta-analysis identified and included 16 studies with 984 patients. The pooled estimate for overall response rate (ORR) was 89%; complete remission (CR) rate was 74%. The 6-month and 12-month progression-free survival (PFS) rates were 69% and 53%, respectively, while the overall survival (OS) rates were 80% and 69%, respectively. Cytokine release syndrome (CRS) of grade 3 or higher was observed in 8% of patients, whereas neurotoxicity of grade 3 or higher was observed in 22% of patients. The risk of bias was assessed as low in 9 studies and moderate in 7 studies. Conclusion: CAR-T therapy exhibited promising efficacy and manageable adverse reactions in patients with R/R MCL. [ABSTRACT FROM AUTHOR]

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological cancer characterized by the abnormal proliferation of plasma cells. Initial treatments often include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite salient progress in diagnosis and treatment, most MM patients typically have a median life expectancy of only four to five years after starting treatment. In recent developments, the success of chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies exemplifies a new paradigm shift in advanced immunotherapy techniques with promising therapeutic outcomes. Ide-cel and cilta-cel stand as the only two FDA-approved BCMA-targeted CAR T-cells for MM patients, a recognition achieved despite extensive preclinical and clinical research efforts in this domain. Challenges remain regarding certain aspects of CAR T-cell manufacturing and administration processes, including the lack of accessibility and durability due to T-cell characteristics, along with expensive and time-consuming processes limiting health plan coverage. Moreover, MM features, such as tumor antigen heterogeneity, antigen presentation alterations, complex tumor microenvironments, and challenges in CAR-T trafficking, contribute to CAR T-cell exhaustion and subsequent therapy relapse or refractory status. Additionally, the occurrence of adverse events such as cytokine release syndrome, neurotoxicity, and on-target, off-tumor toxicities present obstacles to CAR T-cell therapies. Consequently, ongoing CAR T-cell trials are diligently addressing these challenges and barriers. In this review, we provide an overview of the effectiveness of currently available CAR T-cell treatments for MM, explore the primary resistance mechanisms to these treatments, suggest strategies for improving long-lasting remissions, and investigate the potential for combination therapies involving CAR T-cells. [ABSTRACT FROM AUTHOR]

The neurological complications of influenza affect mainly the pediatric Asian population. In the category of influenza-associated encephalopathy, acute necrotizing encephalopathy (ANE) is a rapidly progressive and fulminant brain disorder associated with significant neurological sequelae and mortality. To date, only a few adult cases of influenza-associated ANE have been reported. We describe a 44-year-old woman who presented with rapid progression of consciousness impairment and recurrent generalized convulsions. Influenza was diagnosed three days prior to presentation, and infection with influenza A (H3N2) pdm09 was subsequently confirmed. A diagnosis of ANE was made based on the presence of characteristic brain MRI findings, the exclusion of central nervous system infection, and an elevated serum interleukin-6 level. Pulse steroid therapy followed by tocilizumab was initiated, which led to clinical stabilization and improvement. Genetic testing revealed that the patient carried heterozygous human leukocyte antigen DQB1 03:03 and DRB1 09:01 genotypes. An analysis of the adult cases of influenza-associated ANE in the literature and the present case revealed a wide range of ages (22–71 years), a short interval (median 3 days) between the clinical onset of influenza and ANE, and a high overall mortality rate (32%). The thalamus was the most frequent (91%) location of the lesions. Our report highlights the importance of identifying this devastating but treatable neurological complication of influenza in adults, especially those of Asian descent. As a cytokine storm is the most accepted pathogenic mechanism for ANE, cytokine-directed therapies may be promising treatments for which further investigation is warranted. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor discussing a study on pediatric acute lymphoblastic leukemia (ALL)-associated hemophagocytic lymphohistiocytosis (HLH). The study found that liver enzymes and activated CD8+ T cells were increased in patients with ALL-associated HLH. The authors suggest that liver enzyme elevations could serve as diagnostic markers for this potentially fatal disease. The study has some limitations, including its retrospective design and the unavailability of laboratory data for some patients in the control group. Further investigation is needed to understand the incidence and clinical characteristics of ML-HLH associated with pediatric ALL. [Extracted from the article]

This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre‐clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from the THP‐1 cell line, creating a physiological biological microenvironment. To mimic the three‐dimensional architecture and dynamic expansion and relaxation of the air‐blood‐barrier, they are grown on a stretchable microphysiological lung‐on‐chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti‐inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS‐induced acute lung injury measured best with cytokine IL‐6 release; (2) an inflammation caused by LPS at ALI (air‐liquid interface) to investigate aerosolized anti‐inflammatory treatment, measured with chemokine IL‐8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ‐induced inflammation. [ABSTRACT FROM AUTHOR]

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects. [ABSTRACT FROM AUTHOR]

Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov. Identifier NCT05557110. [ABSTRACT FROM AUTHOR]

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91–87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11–22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0–2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Background: Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ failure, which is triggered by immunotherapy or certain infections. Immune checkpoint inhibitors rarely cause immune-related adverse event- cytokine release syndrome (irAE-CRS). This article presents a case report of irAE-CRS triggered by coronavirus disease 2019 (COVID-19). Case presentation: A 60-year-old man with type 2 diabetes received nivolumab treatment for esophagogastric junction carcinoma and experienced two immune-related adverse events: hypothyroidism and skin disorder. Eleven days before his visit to our hospital, he had a fever and was diagnosed with COVID-19. Five days before his visit, he developed a fever again, along with general malaise, water soluble diarrhea, and myalgia of the extremities. On admission, the patient was in a state of multiple organ failure, and although the source of infection was unknown, a tentative diagnosis of septic shock was made. The patient's condition was unstable despite systemic management with antimicrobial agents, high-dose vasopressors, and intravenous fluids. We suspected CRS due to irAE (irAE-CRS) based on his history of nivolumab use. Steroid pulse therapy (methylprednisolone 1 g/day) was started, and the patient temporarily recovered. However, his respiratory condition worsened; consequently, he was placed on a ventilator and tocilizumab was added to the treatment. His muscle strength recovered to the point where he could live at home, and was subsequently discharged. Conclusion: In patients previously treated with immune checkpoint inhibitors, irAE-CRS should be considered as a differential diagnosis when multiple organ damage is observed in addition to inflammatory findings. It is recommended to start treatment with steroids; if the disease is refractory, other immunosuppressive therapies such as tocilizumab should be introduced as early as possible. [ABSTRACT FROM AUTHOR]

The aim of the study was to conduct of relationship of acute-phase proteins (APPs) with the severity of COVID-19 defined by National Institutes of Health and according to the criteria of MEWS scale, with the presence of a cytokine storm, oxygen therapy and patient survival. We enrolled 96 patients with COVID-19 and 30 healthy people. The samples were taken on the day of admission and after 9 days on average. Not only commonly used APPs such as CRP, procalcitonin and ferritin and also rarely assayed proteins such as transferrin, haptoglobin, α1-acid glycoprotein and α1-antitrypsin, were tested in the study. The levels of APPs depends on the severity of COVID-19 disease, on the presence of cytokine storm and used oxygen therapy. The greatest APPs changes occurred in the most advanced form of the disease, with the presence of a cytokine storm and the most intense oxygen therapy. The results obtained from MEWS scale were not consistent with National Institutes of Health scores. Studies in the second samples showed the quenching of the acute phase reactions and the effectiveness of oxygen therapy. Only two of the examined APPs i.e. procalcitonin and transferrin, differed between surviving and non-surviving patients, and these two predispose to the role of prognostic factors in Covid-19. In conclusion, the concentration of not all acute-phase proteins depends on the severity of COVID-19 disease, presence of cytokine storm, the used of oxygen therapy and only some of them (procalcitonin and transferrin) are related to the survival outcomes. Of the newly tested acute-phase proteins, only transferrin shows significance as a marker of disease severity and mortality in COVID-19 disease. [ABSTRACT FROM AUTHOR]

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes. [ABSTRACT FROM AUTHOR]

The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1β, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1β, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (bsAbs) are an emerging therapy in the treatment of large B-cell lymphomas (LBCLs). There is a gap in the research on the safety and efficacy of bsAbs in adults with LBCL, with current research focusing on the wider non-Hodgkin's lymphoma population. To address this research gap, we conducted a systematic review aiming to evaluate the safety and efficacy outcomes of bsAbs in adults with LBCL. A systematized search was conducted in PubMed, EMBASE, and CENTRAL on 10 April 2024. Interventional clinical trials were eligible for inclusion. Observational studies, reviews, and meta-analyses were excluded. According to the Revised Risk of Bias Assessment Tool for Nonrandomized Studies, the included studies were largely of a high quality for safety outcome reporting, but of mixed quality for efficacy outcome reporting. Due to the heterogeneity of the included studies, the results were discussed as a narrative synthesis. Nineteen early phase studies were evaluated in the final analysis, with a pooled sample size of 1332 patients. Nine bsAbs were investigated across the studies as monotherapy (nine studies) or in combination regimes (10 studies). The rates of cytokine release syndrome were variable, with any grade events ranging from 0 to 72.2%. Infection rates were consistently high across the reporting studies (38–60%). Cytopenias were found to be common, in particular, anemia (4.4–62%), thrombocytopenia (3.3–69%), and neutropenia (4.4–70%). Immune effector cell-associated neurotoxicity syndrome (ICANS) and grade ≥3 adverse events were not commonly reported. Promising efficacy outcomes were reported, with median overall response rates of 95–100% in the front-line and 36–91% in terms of relapsed/refractory disease. The results of this systematic review demonstrate that bsAbs are generally well-tolerated and effective in adults with LBCL. BsAbs appear to have superior tolerability, but inferior efficacy to CAR T-cell therapies in adults with LBCL. Future research on safety and efficacy should focus on evaluating adverse event timing and management, the impact on the patient's quality of life, the burden on the healthcare system, and overall survival outcomes. [ABSTRACT FROM AUTHOR]

The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists. [ABSTRACT FROM AUTHOR]

Introduction Clinical practice guidelines (CPGs) and clinical recommendations (CRs) are developed to aide and guide providers in treating a variety of conditions, including traumatic brain injury (TBI). There is little knowledge on the impact that CPGs and CRs have on provider practice. One TBI recommendation that was able to be tracked in medical record codes was the use of benzodiazepines (BZD). Because of potential for misuse, diversion, addiction, cognitive impairment, and brain healing interference, the DoD and Department of Veterans Affairs (VA) jointly discourage prescribing BZD after TBI. As part of an effort to look at translation of CPG guidance into clinical practice, our objective was to examine the issuance of BZD prescriptions, including dose, type, and prescribing provider, prescribing setting, and primary diagnosis at issuance among U.S. service members with mild Traumatic Brian Injury (mTBI). Materials and Methods Using DoD data sourced from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) databases of the Military Health System (MHS) Medical Data Repository (MDR), we identified all U.S. service members with a first lifetime diagnosis of mTBI from October 1, 2015 to September 30, 2016. Data on prescriptions issued to this group during a period of active treatment for a mTBI were obtained from the Pharmacy Detail Transaction Service (PDTS) databases of the MDR and identified BZD prescriptions based on the American Hospital Formulary Service (AHFS) therapeutic classification system. We validated coding assumptions through structured review of the clinical record contained within the Armed Forces Health Longitudinal Technology Application (AHLTA) of 30 randomly selected cohort members. Results Among U.S. service members, 4.5% filled a BZD prescription while under active medical treatment for a recent mTBI. These service members were more likely female and older when compared to their counterparts not prescribed BZD. Among service members under active treatment for mTBI during the study period, 52.6% (n  = 7,935) filled a prescription; of these, 8.5% (n  = 676) filled a BZD prescription. Of U.S. service members filing a BZD prescription while undergoing active treatment for an mTBI, 64.6% (n  = 437) filled prescriptions for BZD and antidepressants, 54.9% (n  = 371) filled prescriptions for both BZD and NSAIDS, and 42.2% (n  = 285) concurrently filled prescriptions for BZD and opioids. Conclusions This effort to examine the translation of CPG recommendations into practice through evaluation of medical record data indicates that providers are prescribing BZD to patients under active treatment for an acute mTBI. The mTBI CPG recommends that the BZD class of medications be avoided in patients healing from brain injury. However, the team recognizes there are confounding factors that may impact the medications that are prescribed for patients with mTBI. Additional work to understand how CPGs and CRs are received and utilized by providers may elucidate opportunities to close the gap between clinical practice guidance and clinical practice. [ABSTRACT FROM AUTHOR]