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Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38–3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3–0.94 and HR = 0.65; 95% CI, 0.46–0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27–3.19). The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS. [ABSTRACT FROM AUTHOR]

Today, genome editing technologies like zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR) are being used in clinical trials and the treatment of diseases like acquired immunodeficiency syndrome (AIDS) and cancer. CRISPR stands out as one of the most advanced tools for genome editing due to its simplicity and cost-effectiveness. It can selectively modify specific locations in the genome, offering new possibilities for treating human diseases. The CRISPR system uses ribonucleic acid-deoxyribonucleic acid (RNA-DNA) recognition to combat infections, regulate gene expression, and treat cancer. Chimeric antigen receptor (CAR) T-cell therapy, which uses T lymphocytes to eliminate cancer cells, can be improved by combining it with CRISPR technology. However, there are challenges in using CAR-T cells, including a lack of quantity and quality, exhaustion, neurotoxicity, cytokine release syndrome (CRS), B cell aplasia, tumor lysis syndrome, and anaphylaxis. Preclinical studies on CRISPR-edited CAR-T cells show promising results and targeting detrimental regulatory genes can enhance cancer treatment in the future. [Display omitted] • CRISPR technology has opened a new perspective in treating cancer by manipulating the genome. • Chimeric antigen receptors (CARs) are unique receptors designed to be functionally reprogrammed and targeted to a specific tumor antigen. • CAR-T cell therapy is a type of gene therapy in which lymphocyte eradicates cancer cells. • The production of CAR-T cells is one of the most critical applications of CRISPR-Cas9 technology in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Survival in Epstein–Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov , NCT03394365 , and is ongoing. From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23–77) of 14 participants in the HSCT group and 15 (52%, 33–71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7–23·9) and 6·0 months (1·8–18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. Atara Biotherapeutics. [ABSTRACT FROM AUTHOR]

[Display omitted] Engineered T cells expressing chimeric antigen receptor (CAR) exhibit high response rates in B-cell malignancy treatments and possess therapeutic potentials against various diseases. However, the complicated ex vivo production process of CAR-T cells limits their application. Herein, we use virus-mimetic fusogenic nanovesicles (FuNVs) to produce CAR-T cells in vivo via membrane fusion-mediated CAR protein delivery. Briefly, the FuNVs are modified using T-cell fusogen, adapted from measles virus or reovirus fusogens via displaying anti-CD3 single-chain variable fragment. The FuNVs can efficiently fuse with the T-cell membrane in vivo , thereby delivering the loaded anti-CD19 (αCD19) CAR protein onto T-cells to produce αCD19 CAR-T cells. These αCD19 CAR-T cells alone or in combination with anti-OX40 antibodies can treat B-cell lymphoma without inducing cytokine release syndrome. Thus, our strategy provides a novel method for engineering T cells into CAR-T cells in vivo and can further be employed to deliver other therapeutic membrane proteins. [ABSTRACT FROM AUTHOR]

• Infection is very common in alcoholic hepatitis. • Both infection and alcoholic hepatitis are causes of SIRS. • IL-6 may be able to differentiate when infection is present. Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p <0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon‐gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000–1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections. [ABSTRACT FROM AUTHOR]

With the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS). In a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell–associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them. We showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS. The incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying. [ABSTRACT FROM AUTHOR]

Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1–18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov , NCT04340154 , and enrolment has ended. Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6–10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37–41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89–100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4–20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66–91), duration of remission was 80% (68–92), and disease-free survival was 80% (68–92) with transplantation censoring; overall survival was 96% (91–100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7–14) after CD19-directed and 12 days (10–15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Paraguay is currently facing a new outbreak of Chikungunya virus. This report summarizes two severe cases of Chikungunya (CHIKV) infection, confirmed by real-time reverse transcription polymerase chain reaction. We present the cases of patients with acute CHIKV infection and multisystem involvement, with fever, rash, abdominal pain, vomiting, myocarditis, and coronary artery anomalies, very similar to the cases described in MIS-C related to SARS-CoV-2 during the COVID-19 Pandemic. Both patients received IVIG and methylprednisolone, with good clinical response. In this setting of cytokine storm in Chikungunya, can we call it "Multisystem inflammatory syndrome associated with Chikungunya"?. [ABSTRACT FROM AUTHOR]

Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague–Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS. In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups. LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen. Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1β. [ABSTRACT FROM AUTHOR]

Patients with multiple myeloma (MM) treated with anti-B cell maturation antigen (BCMA) and chimeric antigen receptor (CAR) T-cell therapy tend to show delayed platelet recovery. This single-center retrospective observational study included a cohort of patients with MM treated with anti-BCMA CAR-T cells in ChiCTR-OPC-16009113, ChiCTR1800018137, and ChiCTR1900021153. Fifty-eight patients with MM treated with anti-BCMA CAR-T cells were included. Delayed platelet recovery (platelet count not recovering to 50 × 109/L within 28 days) was observed in 36 % of patients. Regression analysis identified several factors that influenced platelet recovery, and accordingly, a Recovery-Model was developed. A high Recovery-Model score indicates a greater risk of delayed platelet recovery after CAR-T cell infusion and reflects the risk of hematologic toxicity. The model's predictive biomarkers included baseline platelet count, baseline hemoglobin level, logarithm of baseline Ferritin level, and cytokine release syndrome grade. Finally, survival analysis showed a significant relationship between overall survival, delayed platelet recovery (p = 0.0457), and a high Recovery-Model score (p = 0.0011). Inflammation-related factors and bone marrow reserves are associated with delayed platelet recovery. Therefore, we developed a model to predict the risk of delayed platelet recovery and hematological toxicity in relapsed/refractory patients with MM after anti-BCMA CAR-T cell treatment. • Thrombocytopenia was common in patients after anti-BCMA CAR-T therapy. • Inflammation-related factors and bone marrow reserve were associated with delayed platelet recovery. • The recovery of platelets correlated with overall survival (OS) in patients after anti-BCMA CAR-T therapy. • A model predicting CAR T-mediated delayed platelet recovery in R/R MM patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov , NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival. [ABSTRACT FROM AUTHOR]

PSMA expression is preserved throughout all stages of prostate cancer. In this phase 1 study of JNJ-63898081, a bispecific antibody binding to PSMA-expressing tumor cells and CD3-expressing T cells, patients with metastatic castration-resistant prostate cancer had frequent cases of cytokine release syndrome, which were manageable, and transient declines in PSA. Treatment-related deaths and radiographic responses were not observed. PSMA is a potential therapeutic target for T-cell redirection in prostate cancer. Introduction: Cancer immunotherapies have limited efficacy in prostate cancer due to the immunosuppressive prostate microenvironment. Prostate specific membrane antigen (PSMA) expression is prevalent in prostate cancer, preserved during malignant transformation, and increases in response to anti-androgen therapies, making it a commonly targeted tumor associated antigen for prostate cancer. JNJ-63898081 (JNJ-081) is a bispecific antibody targeting PSMAexpressing tumor cells and CD3-expressing T cells, aiming to overcome immunosuppression and promoting antitumor activity. Patients and Methods: We conducted a phase 1 dose escalation study of JNJ-081 in patients with metastatic castration-resistance prostate cancer (mCRPC). Eligible patients included those receiving =1 prior line treatment with either novel androgen receptor targeted therapy or taxane for mCRPC. Safety, pharmacokinetics, and pharmacodynamics of JNJ-081, and preliminary antitumor response to treatment were evaluated. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route. Results: Thirty-nine patients in 10 dosing cohorts received JNJ-081 ranging from 0.3 µg/kg to 3.0 µg/kg IV and 3.0 µg/kg to 60 µg/kg SC (with step-up priming used at higher SC doses). All 39 patients experienced =1 treatment-emergent AE, and no treatment-related deaths were reported. Dose-limiting toxicities were observed in 4 patients. Cytokine release syndrome (CRS) was observed at higher doses with JNJ-081 IV or SC; however, CRS and infusion-related reaction (IRR) were reduced with SC dosing and step-up priming at higher doses. Treatment doses > 30 µg/kg SC led to transient PSA decreases. No radiographic responses were observed. Antidrug antibody responses were observed in 19 patients receiving JNJ-081 IV or SC. Conclusion: JNJ-081 dosing led to transient declines in PSA in patients with mCRPC. CRS and IRR could be partially mitigated by SC dosing, step-up priming, and a combination of both strategies. T cell redirection for prostate cancer is feasible and PSMA is a potential therapeutic target for T cell redirection in prostate cancer. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. Both groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed. [ABSTRACT FROM AUTHOR]

The RELIANCE study has demonstrated the activity and safety of relmacabtagene autoleucel (relma-cel) (JW Therapeutics [Shanghai] Co, Ltd, Shanghai, China), a CD19-targeted chimeric antigen receptor T-cell product, in patients with heavily pre-treated relapsed/refractory large B-cell lymphoma (r/r LBCL). This study aimed to report the updated 2-year data of the RELIANCE study. The RELIANCE study (NCT04089215) was an open-label, multi-center, randomized, phase 1/2 registrational clinical trial conducted at 10 clinical sites in China. Adult patients with heavily pre-treated r/r LBCL were enrolled and received lymphodepletion chemotherapy followed by infusion of 100 × 106 or 150 × 106 relma-cel. The primary endpoint was objective response rate (ORR) at 3 months, as assessed by investigators. Secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety profiles. From November 2017 to January 2022, a total of 68 patients were enrolled, and 59 patients received relma-cel infusion. As of March 29, 2022, a total of 59 patients had a median follow-up of 17.9 months (range, 0.3–25.6). ORR was 77.59% (95% confidence interval [CI], 64.73–87.49) and complete response rate was 53.45% (95% CI, 39.87–66.66). Median DoR was 20.3 months (95% CI, 4.86–not reached [NR]) and median PFS was 7.0 months (95% CI, 4.76–24.15). Median OS was NR and 1-year and 2-year OS rates were 75.0% and 69.3%, respectively. Three (5.1%) patients experienced grade ≥3 cytokine release syndrome and two (3.4%) patients had grade ≥3 neurotoxicity. The updated data of the RELIANCE study demonstrate durable response with and manageable safety profile of relma-cel in patients with heavily pre-treated r/r LBCL. [ABSTRACT FROM AUTHOR]

Using our lab's feeder-free and chemically defined differentiation protocol, we can robustly generate mature conventional T cells from human induced pluripotent stem cells (hiPSCs). Through CRISPR/Cas gene editing, we integrated a functional iTCR clone, derived from primary human iNKT cells, into the TCR alpha constant (TRAC) locus of hiPSCs. Differentiation of the TRAC engineered hiPSCs using our system yielded mature T cells expressing our iTCR clone. Ongoing studies are investigating strategies to improve selection and expansion of this mature population by providing specific niches during selection and maturation. Further comparison with other TRAC engineered hiPSC-derived T cells by phenotypic and functional assays will help us to elucidate how iTCR expression regulates iNKT cell development, including the acquisition of innate NK cell receptors and cytokine responses post-stimulation. By understanding the ontogeny and downstream signaling of the iTCR in T cells during development, including positive selection and expansion capacity, we can harness specific properties of unconventional T cells to develop more effective off-the-shelf T cell therapeutics for various diseases. Epidermal growth factor receptor (EGFR) is a promising target for treating various solid cancers, including colorectal (CRC), lung, pancreatic, and breast cancer. However, the development of EGFR-specific T-cell products still faces several challenges, such as laborious cell culture procedures, concerns regarding lentivirus-based gene transfection, or insufficient purity of EGFR-specific T cells. Our aim is to develop a novel bi-specific antibody armed-T technology platform that simplifies the manufacturing process to produce highly pure cancer-specific T cell products with the benefits of time-saving, safety, and high anti-cancer efficacy. In this study, we have sucessfully demonstrated that EGFR Armed-T cells, which arm patient's PBMCs with our unique anti-EGFR/anti-CD3 bispecific antibody (BsAb), displayed highly efficient tumor-killing ability in various EGFR-positive cancer cell lines, including colorectal cancer (HT-29, HCT116, COLO, LS174T), lung cancer (A549, CL1-5, HCC827), pancreatic cancer (MiaPaCa, Panc1), and triple-negative breast cancer (MDA-MB-231, MDA-MB-468) in vitro. We found that EGFR Armed-T cells, but not normal T cells, can largely accumulate at EGFR-positive tumors and significantly inhibit tumor growth in SCID mice bearing with human colorectal, breast, or pancreatic tumors, respectively. Furthermore, EGFR Armed-T cells did not cause significant cytokine release syndrome or serum/tissue toxicity in these SCID mice. To initiate a first-in-human (FIH) clinical trial, we successfully manufactured the EGFR Armed-T cell products under GMP conditions. We further proved that these BsAb-armed T cells, but not the naïve T cells, can effectively eliminate human colorectal cancer cells. In conclusion, through the success of our CMC qualification, we are approaching the FIH trial, which was designed for colorectal cancer patients with EGFR downstream mutations (KRAS, NRAS or BRAF). [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells can quickly and directly eradicate tumour cells without recognising tumour-specific antigens. NK cells also participate in immune surveillance, which arouses great interest in the development of novel cancer therapies. The chimeric antigen receptor (CAR) family is composed of receptor proteins that give immune cells extra capabilities to target specific antigen proteins or enhance their killing effects. CAR-T cell therapy has achieved initial success in haematological tumours, but is prone to adverse reactions, especially with cytokine release syndrome in clinical applications. Currently, CAR-NK cell therapy has been shown to successfully kill haematological tumour cells with allogeneic NK cells in clinical trials without adverse reactions, proving its potential to become an off-the-shelf product with broad clinical application prospects. Meanwhile, clinical trials of CAR-NK cells for solid tumours are currently underway. Here we will focus on the latest advances in CAR-NK cells, including preclinical and clinical trials in solid tumours, the advantages and challenges of CAR-NK cell therapy and new strategies to improve the safety and efficacy of CAR-NK cell therapy. [ABSTRACT FROM AUTHOR]

Although acute encephalopathy (AE) is the most serious disorder associated with a viral infection in childhood and often causes death or neurological sequelae, standard treatments have not been established. In 2016, the Japanese Society of Child Neurology published the "Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood 2016" (AE GL 2016). We conducted a questionnaire survey to evaluate the status of the treatment of pediatric AE in 2021 and the changes in treatment before and after the publication of the AE GL 2016. In October 2021, questionnaires were mailed via the web to members of two mailing lists who were involved in the practice of pediatric neurological disorders. Most Japanese physicians (98 %) engaged in the treatment of pediatric AE used the AE GL 2016 as a clinical reference. From 2015 to 2021, the number of institutions that implemented targeted temperature management (TTM), vitamin administration, and continuous electroencephalographic monitoring increased significantly. Regarding the targeted temperature for TTM, the proportion of patients who were treated with normothermia (36.0–37.0 °C) increased from 2015 (55 %) to 2021 (79 %). The use of corticosteroids in patients with AE caused by a cytokine storm, which is recommended in the AE GL 2016, had already been implemented in most institutions by 2015. The AE GL 2016 could be used to disseminate the knowledge accumulated to date. Evidence of the efficacy and proper indication criteria for the treatment of AE is insufficient and must be further accumulated. [ABSTRACT FROM AUTHOR]

Due to severe immune dysfunction, cytokine release syndrome (CRS) may lead to severe clinical outcomes, including death. The exact mechanisms of CRS remain elusive. Thus, the identification of CRS risk factors and potential risk populations are needed in CRS management. In addition to well-conceived immune factors, animal studies have revealed that stress hormone catecholamines also possess pleiotropic immunoregulatory functions through various mechanisms, such as inducing production of proinflammatory cytokines and enhancing immune cell migration. This suggests that targeting catecholamines might represent a viable candidate approach to alleviate CRS and possibly other severe inflammatory conditions. Primary diseases such as obesity, diabetes, and hypertension are associated with low-grade inflammation and immune dysfunction in humans. We argue that these comorbidities are likely to promote/exacerbate CRS. Thus, controlling primary disease deterioration might be beneficial in CRS prevention. Cytokine release syndrome (CRS) is a state of severe inflammation that can be life-threatening. There is a lack of specific therapeutic strategies; therefore, current CRS treatments are empirically adopted from treatments for other inflammatory disorders. Recent studies show that conditions such as stress, obesity, diabetes, and hypertension exacerbate inflammation and may constitute risk factors for CRS. An in-depth understanding of how these conditions might modulate CRS outcomes could facilitate the design of putative CRS therapeutic strategies from a renewed perspective. Cytokine release syndrome (CRS) is a severe clinical syndrome marked by drastic elevation of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). Despite the current empirical therapeutic strategies, prediction of CRS onset and identification of high-risk individuals are not satisfactory due to poor understanding of the mechanisms underlying CRS-related immune dysfunction and risk factors for CRS. Recent studies have suggested that conditions such as stress, obesity, diabetes, and hypertension may contribute to the development of CRS. Here, we discuss potential connections between these conditions and CRS pathogenesis, with a focus on stress hormone catecholamine-mediated effects, hoping that the design of CRS therapeutic approaches ensues from a renewed perspective. [ABSTRACT FROM AUTHOR]

The considerable efficacy of B-cell maturation antigen–targeted chimeric antigen receptor (CAR)–T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. This retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR–T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). Among 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR–T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR–T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. Our findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome, also called cytokine storm, could cause lung tissue damage, acute respiratory distress syndrome (ARDS) and even death during SARS-CoV-2 infection. However, the underlying mechanisms of cytokine storm still remain unknown. Among these cytokines, the function of TNF-α and type I IFNs especially deserved further investigation. Here, we first found that TNF-α and IFN-β synergistically induced human airway epithelial cells BEAS-2B death. Mechanistically, the combination of TNF-α and IFN-β led to the activation of caspase-8 and caspase-3, which initiated BEAS-2B apoptosis. The activated caspase-8 and caspase-3 could further induce the cleavage and activation of gasdermin D (GSDMD) and gasdermin E (GSDME), which finally resulted in pro-inflammatory pyroptosis. The knock-down of caspase-8 and caspase-3 could effectively block the activation of GSDMD and GSDME, and then the death of BEAS-2B induced by TNF-α and IFN-β. In addition, pan-caspase inhibitor Z-VAD-FMK (ZVAD) and necrosulfonamide (NSA) could inhibit BEAS-2B death induced by TNF-α and IFN-β. Overall, our work revealed one possible mechanism that cytokine storm causes airway epithelial cells (AECs) damage and ARDS. These results indicated that blocking TNF-α and IFN-β-mediated AECs death may be a potential target to treat related viral infectious diseases, such as COVID-19. • We found that TNF-α and IFN-β synergistically initiated human airway epithelial cells (AECs) death by caspase-8/3-mediated apoptosis and GSDMD/E-mediated pyroptosis. • The special inhibitors could inhibit AECs death induced by these inflammatory cytokines. • Our work revealed possible mechanism that cytokines causes AECs damage. • Blocking TNF-α/IFN-β-mediated AECs death may be a potential target to treat related diseases. [ABSTRACT FROM AUTHOR]

The massive release of pro-inflammatory cytokines is a crucial step in triggering the inflammatory cascade in sepsis. Exploring the key molecules regulating the expression and release of multiple cytokines has important value for revealing the mechanism of the cytokine storm in sepsis. This study aimed to investigate the role of multifunctional nuclear protein non-POU domain containing octamer-binding protein (NONO) in the sepsis cytokine storm and to elucidate the underlying mechanism. We found that NONO expression in tissues and cells of sepsis mice was significantly upregulated. Downregulation of NONO expression inhibited the mRNA expression of multiple cytokines, including IL-6, IL-1β, MCP-1, MIP-1α, and MIP-1β in inflammatory cells from mice and human leukemic monocyte-THP1 cells challenged with lipopolysaccharide (LPS), and significantly decreased the level of these cytokines and TNF-α in the supernatant of THP1 cells challenged by LPS. Nono knockout also reduced the levels of TNF-α, IL-6, MIP-1α, and MIP-1β in serum, alleviated hepatocyte edema, and improved the survival rate of sepsis mice. Reduced NONO expression decreased the phospho-ERK1/2 level in inflammatory cells from sepsis mice or THP1 cells challenged by LPS. Phospho-ERK1/2 inhibitor decreased the mRNA expression and concentration of cytokines in the culture supernatant of LPS-induced THP1 cells, similar to the effect of NONO knockdown. After LPS challenge, the levels of phospho-ERK1/2 and NONO were increased, with obvious colocalization in the nucleus and vesicular-like organelles in macrophages. NONO knockdown decreased nuclear translocation of phospho-ERK1/2 in LPS-challenged THP1 cells. These results suggest that NONO is a potentially critical molecule involved in multiple cytokine production in sepsis. Upregulated NONO in sepsis may promote the expression and release of multiple cytokines to participate in a sepsis cytokine storm by promoting ERK1/2 phosphorylation. • NONO expression was upregulated in sepsis mice. • Nono knockout inhibited the expression and release of proinflammatory cytokines, and reduced the mortality of sepsis mice. • NONO knockdown inhibited the expression and release of proinflammatory cytokines in lipopolysaccharide-induced THP1 cells. • Reduced NONO expression inhibited the phosphorylation of ERK1/2 in mice and THP1 cells challenged by lipopolysaccharide. • NONO and phospho-ERK1/2 colocalized in macrophages challenged by lipopolysaccharide. [ABSTRACT FROM AUTHOR]

Vasoactive peptides play an important role in a wide range of physiological and pathological conditions. Due to its known functions, the calcitonin gene-related peptide (CGRP) has been suggested as a possible modulator of the hyperimmune response in COVID-19 and thus, blocking its action may lessen the pulmonary effects of COVID-19. To compare the circulating levels of CGRPα and CGRPβ in healthy controls compared to hospitalized COVID-19 patients. The study also analyzed how different comorbidities and treatments may affect these concentrations in cases of COVID-19 infection with pulmonary involvement Serum samples were collected from the antecubital vein of 51 control subjects (mean age = 55 ± 14 years; range = 26–77; 56.9% female) and 52 patients hospitalized with COVID-19 infection (mean age = 55 ± 13; range = 23–77; 55.8% female) from December 2020 to May 2021. Enzyme-linked immunosorbent assays (ELISAs) were used for CGRPα (Abbexa, UK) and CGRPβ (CUSABIO, China) measurements. Comorbidities, symptoms, and treatments of infection were listed. The results showed that the serum levels of both isoforms of CGRP were significantly higher in patients with COVID-19 (α: 57.9 ± 35.8 pg/mL; β: 6.1 ± 2.6 pg/mL) compared to controls (α: 41.8 ± 25.4 pg/mL; β: 4.5 ± 2.4 pg/mL) (p <0.01). Also, the presence of arterial hypertension (HT), obesity, or corticosteroid treatment significantly alter the serum concentration of CGRPα in the subgroups compared to controls. The elevated serum CGRP levels found in our COVID-19 group compared to controls may suggest that CGRP plays a role in the pathophysiology of the disease, more specifically, in the cytokine storm and in the pulmonary involvement. Future studies should focus on the source of this CGRP elevation. [ABSTRACT FROM AUTHOR]

Secondary haemophagocytic lymphohistiocytosis (sHLH) is a life-threatening disorder described in the setting of infections, neoplastic and immune dysregulations. Recently, sHLH has been reported following chimeric antigen receptor T-cell (CAR-T) therapy as a severe manifestation of cytokine release syndrome (CRS) which generally occurs during the early phase after a CAR-T infusion. CAR-T therapy for both relapse/refractory acute lymphoblastic B-cell leukaemia (B-ALL) and non-Hodgkin lymphoma, (diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL)), has been approved by FDA and EMA as a third line treatment. CRS is on-target off-tumour side effect of CAR-T therapy which results in an acute state of hyperinflammation due to both tumour lysis and the proliferation of CAR-T cells. Its clinical presentation has a wide spectrum of severity, in the worst case it could rapidly lead to a multiorgan failure and progress to a fatal sHLH. Here, we present a late occurrence of sHLH after CAR-T treatment. [ABSTRACT FROM AUTHOR]

Considering the high impact that severe Coronavirus disease 2019 (COVID-19) cases still pose on public health and their complex pharmacological management, the search for new therapeutic alternatives is essential. Mesenchymal stromal cells (MSCs) could be promising candidates as they present important immunomodulatory and anti-inflammatory properties that can combat the acute severe respiratory distress syndrome (ARDS) and the cytokine storm occurring in COVID-19, two processes that are mainly driven by an immunological misbalance. In this review, we provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation that occurs in COVID-19, discussing the potential that the cytokines and growth factors that constitute the MSC-derived secretome present to treat the disease. Moreover, we revise the latest clinical progress made in the field, discussing the most important findings of the clinical trials conducted to date, which follow 2 different approaches: MSC-based cell therapy or the administration of the secretome by itself, as a cell-free therapy. • Provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation in COVID-19. • Discuss the potential of the cytokines and growth factors that constitute MSC-derived secretome to treat the disease. • Revise the latest clinical progress made in the field, discussing the most important findings conducted to date. [ABSTRACT FROM AUTHOR]

• RT as a bridging strategy can reduce severe CRS and improve PFS of patients. • RT as a bridging strategy can improve PFS and OS in patients with bulky disease. • Conducting RT as a bridging regimen was an independent factor predicted better PFS. We aimed to analyze the safety and efficacy of a radiation bridging regimen with or without chemotherapy compared with chemotherapy alone prior to CAR T-cell treatment for relapsed/refractory aggressive B-cell lymphoma (r/r ABL). In this study, 45 out of 105 patients enrolled in CD19/22 CAR T-cell "cocktail" clinical trial were excluded, including 34 patients without bridging treatment. Total 60 patients receiving CAR T-cell therapies with bridging regimens as chemotherapy alone (C-CAR-T group, n = 31), and radiotherapy with or without chemotherapy (R-CAR-T group, n = 29) between February 2017 and October 2020 were retrospectively analyzed. No significant toxicities were identified in the R-CAR-T group, and no patients in either group experienced CAR-T-related deaths. However, the R-CAR-T group showed a lower incidence of cytokine release syndrome (CRS) of grade ≥ 3 relative to the C-CAR-T group (0% vs 19.4%, P = 0.036). The incidence of neurological toxicity was 9.9% and 6.9% in the C-CAR-T group and R-CAR-T group, respectively (P = 0.697). The R-CAR-T group achieved a higher overall response rate (ORR) at the day 30 assessment (82.8% vs 45.2%, P = 0.0025). Further analyzing the outcomes, the R-CAR-T group presented a better 1-year progression-free survival (PFS) rate than the C-CAR-T group (46.9% vs 22.6%, P = 0.0356). Intriguingly, the bridging radiation regimen extremely improved the 6-month PFS (50.8% vs 16. 7%, P = 0.0369) and 1-year overall survival (OS) (56.3% vs 33.3%, P = 0.0236) rates in patients with bulky disease. The study also found that conducting radiotherapy as a bridging regimen was an independent factor that predicted better PFS (HR: 0.534, 95% CI: 0.289–0.987, P = 0.045). Our results provide and strengthen novel insights that the use of radiotherapy as a bridging strategy was demonstrated to reduce the incidence of severe CRS and improve the PFS of patients. In subgroup analysis, it was confirmed that radiotherapy can improve PFS and OS in patients with bulky disease. These findings open new avenues to improve the efficacy and safety of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

• Treatment of adults with severe COVID-19 and cytokine storm were compared. • In all, 102/463 patients received tocilizumab, and 361 of 463 received baricitinib. • At 28 days, there was no difference in all-cause mortality between subgroups. • No differences regarding side effects were observed between groups. Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib. A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications. Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P -value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P <0.01), rate of major infectious complications was similar (32/102, 31.4% vs 96/361, 26.6%; P -value = 0.34). In logistic regression, the immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan–Meier analysis revealed statistically similar survival distributions. All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm. [ABSTRACT FROM AUTHOR]

The infusion of chimeric antigen receptor (CAR) T cells that target specific tumor-associated antigens is a promising strategy that has exhibited encouraging results in clinical trials. However, few studies have focused on the effectiveness and safety of CD20 CAR T cells in rituximab-refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients, particularly those treated with rituximab for a short time. This prospective study aimed to assess the effectiveness and toxicity of CD20 CAR T cells in R/R B-NHL patients previously treated with rituximab. The authors conducted a prospective, single-center phase I study on the effectiveness and toxicity of CD20 CAR T cells in rituximab-treated R/R B-NHL patients (no. ChiCTR2000036350). A total of 15 patients with R/R B-NHL were enrolled between November 21, 2017, and December 1, 2021. An overall response rate of 100% was shown in enrolled patients, with 12 (80%) achieving complete remission and three (20%) achieving partial remission for the best response. The median follow-up time was 12.4 months. Progression-free survival and overall survival were not yet reached by the data cutoff day. No patient developed grade 4 cytokine release syndrome, and only one patient had immune effector cell-associated neurotoxicity syndrome. All enrolled B-NHL patients who were previously R/R to rituximab achieved different degrees of clinical response with tolerable toxicities. Notably, patients who had received rituximab within 3 months had a poorer prognosis. [ABSTRACT FROM AUTHOR]

Chimeric receptor T cells (CAR-T) can effectively cure leukemia; however, there are two limitations: a complicated preparation process ex vivo and cytokine release syndrome (CRS). In this study, we constructed a lipid nanoparticle system modified by CD3 antibody on the surface, loading with the plasmid containing the combination gene of interleukin 6 short hairpin RNA (IL-6 shRNA) and CD19-CAR (AntiCD3-LNP/CAR19 + shIL6). The system targeted T cells by the mediation of CD3 antibody and stably transfected T cells to transform them into CAR-T cells with IL-6 knockdown, thus killing CD19-highly expressed leukemia tumor cells and reducing CRS caused by IL-6. In vivo experiments showed that AntiCD3-LNP/CAR19 + shIL6 could stably transfect T cells and produce CAR-T within 90 days to kill the tumor. This significantly prolonged the survival time of leukemia model mice and demonstrated the prepared LNP exhibited the same anti-tumor effect as the traditional CAR-T cells prepared ex vivo. In this study, CAR-T cells were directly produced in vivo after intravenous injection of the lipid nanoparticles, without the need of using the current complex process ex vivo. Additionally, IL-6 expression was silenced, which would be helpful to reduce the CRS and improve the safety of CAR-T therapy. This method improves the convenience of using CAR-T technology and is helpful in further promoting the clinical application of CAR-T. [Display omitted] • New technology is required for CAR-T cells to avoid its complex preparation process and control CRS. • The LNPs modified by CD3 antibody transfected T cells and produced CAR-T cells in vivo. • The CAR-T cells produced by LNPs showed an anti-tumor effect and reduced the incidence of CRS. [ABSTRACT FROM AUTHOR]

The respiratory illness triggered by severe acute respiratory syndrome virus-2 (SARS-CoV-2) is often particularly serious or fatal amongst patients with pre-existing heart conditions. Although the mechanisms underlying SARS-CoV-2-related cardiac damage remain elusive, inflammation (i.e. 'cytokine storm') and oxidative stress are likely involved. Here we sought to determine: 1) if cardiomyocytes are targeted by SARS-CoV-2 and 2) how inflammation and oxidative stress promote the viral entry into cardiac cells. We analysed pro-inflammatory and oxidative stress and its impact on virus entry and virus-associated cardiac damage from SARS-CoV-2 infected patients and compared it to left ventricular myocardial tissues obtained from non-infected transplanted hearts either from end stage heart failure or non-failing hearts (donor group). We found that neuropilin-1 potentiates SARS-CoV-2 entry into human cardiomyocytes, a phenomenon driven by inflammatory and oxidant signals. These changes accounted for increased proteases activity and apoptotic markers thus leading to cell damage and apoptosis. This study provides new insights into the mechanisms of SARS-CoV-2 entry into the heart and defines promising targets for antiviral interventions for COVID-19 patients with pre-existing heart conditions or patients with co-morbidities. • To determine if cardiomyocytes are targeted by SARS-CoV-2. • The role of inflammation and oxidative stress in promoting the viral entry. • The consequences on cell damage. [ABSTRACT FROM AUTHOR]

The existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is conflicting. Therefore, we reviewed all available evidence to examine the association between BT and CAR-T therapy outcomes by systematic review and meta-analysis approach. Two reviewers independently searched Embase, PubMed, Web of Science, and Cochrane library to identify all records that described BT for LBCL treated with CAR-T. We then applied a fixed- or random-effects meta-analysis to estimate the pooled hazard ratios (HRs) and rate ratio (RRs) for efficacy and safety endpoints and assessed differences across various BT modalities. The Newcastle-Ottawa Scale was used to evaluate study quality. Twenty-six reports from 24 studies involving 2014 patients were included in the analysis. Pooled results showed that patients requiring BT had significantly worse 1-year overall survival rate (RR = 0.76, 95% confidence interval [CI] 0.68–0.85, P < 0.001), 1-year progression-free survival rate (RR = 0.71, 95% CI 0.60–0.85, P < 0.001), progression-free survival (HR = 1.35, 95% CI 1.07–1.69, P = 0.01), overall response rate (RR = 0.88, 95% CI 0.81–0.95, P = 0.001), complete response rate (RR = 0.78, 95% CI 0.65–0.93, P = 0.005), and grade ≥3 immune effector cell-associated neurotoxicity syndrome (RR = 1.43, 95% CI 1.10–1.87, P = 0.007), and tended to have poorer overall survival (HR = 1.42, 95% CI 0.99–2.02, P = 0.056) and grade ≥3 cytokine release syndrome (RR = 1.59, 95% CI 0.92–2.75, P = 0.096). Prolonged cytopenias were the common toxicity event associated with BT. Radiotherapy may serve as a promising BT option that can provide safe and effective disease control for patients with LBCL before CAR-T infusion. The inconsistency of patient baselines in the current study hindered further comparisons between different BT modalities. Most of the available evidence was rated as low quality because of concerns over low comparability. BT appears to be associated with comparatively poor efficacy and safety outcomes after CAR-T infusion. However, due to the considerable heterogeneity between the BT and non-BT cohorts at disease baseline, no definitive conclusions can be made for the true impact of BT on CAR-T until further randomized studies are conducted. [ABSTRACT FROM AUTHOR]

Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization. • Bendamustine is an effective lymphodepletion regimen before tisagenlecleucel in patients with relapsed/refractory lymphomas. • Bendamustine lymphodepletion has reduced hematological toxicities and infectious complications compared with Flu/Cy. • CRS, neurotoxicity, and hospital utilization are lower in patients treated with bendamustine compared with Flu/Cy. [ABSTRACT FROM AUTHOR]

• COVID-19 is characterized by a systemic, uncontrolled inflammatory response of the innate and adaptive immunity, leading to exaggerated inflammation, named cytokine release syndrome. In the absence of an effective treatment, many off-label agents from the drug armamentarium of rheumatology are currently used. • Therapeutic strategies are divided into those that aim to target viral entry and its life cycle into the host cell and to those that target the inflammatory reaction. • The first approach comprises antiviral therapies aiming to reduce the viral replication and its load, among them the anti-SARS-CoV-2 mAbs. • The second approach focuses on the inhibition of cytokine cell receptors and it's signaling, leading to reduction of cytokine production. In this setting, systemic glucocorticoids, IL-6R antagonists and JAK inhibitors play a cardinal role. The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled inflammatory response of the innate and adaptive immunity with the release of a plethora of proinflammatory cytokines termed "cytokine storm". In the absence of an effective treatment, many off-label agents from the armamentarium of rheumatology are used. Here, from the perspective of a rheumatologist, we will discuss the current therapeutic strategies in critically ill patients with SARS-CoV-2 pneumonia. Thus, we will discuss the agents that aim to target viral entry and its replication into the host cell and those focusing and targeting the inflammatory response. In this setting, many agents have been used with promising results but, not all have been approved by the International Authorities and Institutions. In the first step (viral entry), SARS-CoV-2 monoclonal antibodies and remdesivir have been approved to be used and, in the second step, corticosteroids along with interleukin-6 inhibitors, or Janus Kinase inhibitors are currently used. [ABSTRACT FROM AUTHOR]

Acute necrotizing encephalopathy (ANE) is a pediatric neurological disease, presumably caused by cytokine storms, with a poor prognosis. Immunomodulatory therapy, including therapeutic plasma exchange (TPE), could be an effective treatment. Two patients with influenza-associated ANE were treated. The ANE severity scores were 3 and 8 in case 1 (a 3-y-old boy) and case 2 (a 7-y-old boy), respectively. In case 1, intravenous methylprednisolone and TPE were initiated at 8 and 16 h, respectively, after the onset of impaired consciousness. In case 2, multiple organ failure and septic shock persisted even after infusion of fluids and inotropic agents. Intravenous methylprednisolone and TPE were started at 5 and 9 h, respectively, after the onset of impaired consciousness, which improved the inotrope-refractory septic shock. Patient 1 and 2 achieved complete neurological recovery within 4 weeks and after 3 months, respectively. In both patients, cytokine levels were serially measured. There were increased serum interleukin (IL)-6 and IL-10 levels in both patients; patient 1 showed increased IL-6 levels in the initial cerebrospinal fluid sample. There was a post-treatment decrease in serum IL-6 levels in both cases. Early intensive immunomodulatory therapy with TPE may improve neurological outcomes in pediatric influenza-associated ANE. Further studies are required to establish the efficacy of TPE for ANE. [ABSTRACT FROM AUTHOR]

Background: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies.Methods: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing.Findings: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred.Interpretation: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies.Funding: F Hoffmann-La Roche and Genentech. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.Methods: PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m2 and intravenous cyclophosphamide 300 mg/m2 daily for 3 days) followed 2-7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8+ and CD4+ CAR+ T cells for a total target dose of 100 × 106 CAR+ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103.Findings: Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.Interpretation: These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Funding: Juno Therapeutics, a Bristol-Myers Squibb company. [ABSTRACT FROM AUTHOR]

• For the first time, established a predictive model to anticipate the cytokine storms in the acute phase of SFTS patients. • By visualizing the predictive model through a nomogram, it becomes more convenient and user-friendly. • The predictive capacity of the model was evaluated based on the outcomes of 48 cytokines in the validation cohort. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease known for its high mortality rate and its correlation with Cytokine Storms (CS). Timely detection of CS is crucial for improving the prognosis of the disease. The objective of this investigation was to develop a model for identifying cytokine storms in the acute phase of SFTS. A total of 245 patients diagnosed with SFTS were included in this study between January 2020 and July 2022. Among them, 184 patients were part of the training set, while 61 patients were part of the validation set. Variables identified by LASSO were subsequently included in a multivariate logistic regression analysis to determine independent predictors. Subsequently, a nomogram was then developed to predict the likelihood of CS in SFTS patients. The predictive efficacy and clinical applicability of the nomogram model were further assessed through ROC analysis and the DCA curve. Following LASSO analysis, a total of 11 indicators were included in multivariate logistic regression analysis. The findings indicated that PLT (OR 0.865, P < 0.001), LDH (OR 1.002, P < 0.001), Na+ (OR 1.155, P = 0.005), and ALT (OR 1.019, P < 0.001) serve as independently predictors of CS in the acute phase of SFTS. Furthermore, a nomogram named the PLNA was constructed by integrating these four factors. The PLNA model exhibited favorable predictive accuracy with an AUC of 0.958. Moreover, the PLNA model exhibited excellent clinical applicability in both the training and validation sets, as evidenced by the DCA curve. The PLNA model, constructed using clinical indicators, can predict the probability of cytokine storm in the acute phase of SFTS patients. [ABSTRACT FROM AUTHOR]

A drug pair is a fundamental aspect of traditional Chinese medicine prescriptions. Scutellaria baicalensis Georgi and Coptis chinensis Franch, commonly used as an herb couple (SBCC), are representative heat-clearing and dampness-drying drugs. They possess functions such as clearing heat, drying dampness, purging fire, and detoxifying. These herbs are used in both traditional and modern medicine for treating inflammation. This study investigated the effects of SBCC on cytokine storm syndrome (CSS) and explored its potential regulatory mechanism. We assessed the impact of SBCC in a sepsis-induced acute lung injury mouse model by administering an intraperitoneal injection of LPS (15 mg/kg). The cytokine levels in the serum and lungs, the wet-to-dry ratio of the lungs, and lung histopathological changes were evaluated. The macrophages in the lung tissue were examined through transmission electron microscopy. Western blot was used to measure the levels of the CD39/NLRP3/GSDMD pathway-related proteins. Immunofluorescence imaging was used to assess the activation of pro-caspase-1 and ASC and their interaction. AMP-Glo™ assay was used to screen for active ingredients in SBCC targeting CD39. One of the ingredients was selected, and its effect on cell viability was assessed. We induced inflammation in macrophages using LPS + ATP and detected the levels of proinflammatory factors. The images of cell membrane large pores were captured using scanning electron microscopy, the interaction between NLRP3 and ASC was detected using immunofluorescence imaging, and the levels of CD39/NLRP3/GSDMD pathway-related proteins were assessed using Western blot. SBCC administration effectively mitigated LPS-induced cytokine storm, pulmonary edema and lung injury. Furthermore, it repressed the programmed death of lung tissue macrophages by inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. Based on the results of the AMP-Glo™ assay, we selected wogonoside for further valuation. Wogonoside alleviated LPS + ATP-induced inflammatory damage by regulating the inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. However, its effect on NLRP3 is not mediated though CD39. SBCC and its active small-molecule ingredient, wogonoside, improved CSS by regulating the NLRP3/GSDMD pyroptosis pathway and its upstream CD39 purinergic pathway. It is essential to note that the regulatory effect of wogonoside on NLRP3 is not mediated by CD39. [Display omitted] [ABSTRACT FROM AUTHOR]

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE. • Infusion related reactions and cytokine release syndromes (CRS) should be distinguished. • Cytokine release syndrome is the most common reaction with T-cell engagers (TCE). • Cytokine release syndromes is confined to first step-up dosages of T-cell engagers. • Most common toxicities with TCE are CRS, ICANS, infections, tumor flare reactions. • As compared with CAR-T cells, TCE generate less frequently severe CRS or ICANS. [ABSTRACT FROM AUTHOR]

• CAR-T therapy offers durable remissions in refractory hematological malignancies. • Meta-analyses show significant efficacy in various hematologic cancers. • CAR T-cell therapy improves quality of life for blood cancer patients. • Encouraging results in CD22-targeting CAR T-cell therapy for B-cell malignancies. • Long-term studies reveal durable remissions but also persistent adverse effects. Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. [ABSTRACT FROM AUTHOR]

• Heterostructured nano-enzyme CuS@ZnS could be explored for NIR-induced photocatalytic activity in the hydrogen evolution reaction. • Simultaneously clearing lactate and regulating the polarization of macrophage cells can improve long-term therapeutic outcomes. • Generated hydrogen could scavenge intracellular ROS and inhibit cytokine storms, thus alleviating inflammation of CIA mouse. Lactate (LA) undergoes abnormal metabolism in the microenvironment of rheumatoid arthritis (RA), and its excessive accumulation activates a cascade of intracellular signals, acting as an inflammatory enhancer. Simultaneously clearing LA and regulating the polarization of macrophage cells can improve long-term therapeutic outcomes. Here, we developed photocatalytic biomimetic nano enzymes to address multiple factors in RA by generating hydrogen to control innate immunity and reducing LA to restore the immune system. Heterostructured nanocrystals using plasmonic copper and zinc monosulfide could be explored for anomalous plasmon-induced electron transfer for NIR-induced photocatalytic activity in the hydrogen evolution reaction. In our study, overexpressed LA as a sacrificial agent for NIR photocatalytic therapy is depleted; generated hydrogen could scavenge intracellular reactive oxygen species, regulate polarization of M1 to M2 macrophages that could inhibit cytokine storms, thus alleviating inflammation of collagen induced mouse model. This "two-for-one" photocatalytic biomimetic nanoenzyme strategy of oxidative consumption of LA and targeted delivery of hydrogen opens up a potential strategy for treating progressive arthritis. [ABSTRACT FROM AUTHOR]

Abstract Pro-inflammatory M1 macrophages possess the ability to change the immunosuppressive tumor microenvironment by releasing various inflammatory factors simultaneously, which can effectively inhibit tumor progression and relapse. Promoting macrophage polarization towards M1 may be an effective way to treat Melanoma. However, the risk of cytokine storm caused by the proliferation and excessive activation of M1 macrophages greatly limits it as a biosafety therapeutic strategy in anti-tumor immunotherapy. Therefore, how to engineer natural M1 macrophage to a biocompatible biomaterial that maintains the duration time of tumor suppressive property duration time still remains a huge challenge. To achieve this goal, we developed an injectable macroporous hydrogel (M1LMHA) using natural M1 macrophage lysates and alginate as raw materials. M1LMHA had excellent biocompatibility, adjustable degradation rate and could sustainably release varieties of natural inflammatory factors, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), etc. M1LMHA could repolarize anti-inflammatory M2 macrophages to M1 macrophages by the synergistic effect of released tiny inflammatory factors via the NF-κB pathway. This study supported that M1LMHA might be an effective and safe tool to activate tumor-associated immune cells, improving the efficiency of anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia. [Display omitted] • SARS-CoV-2 infection of mice and Syrian hamsters activates the Ire1α-Xbp1 arm of UPR. • Ire1α-Xbp1 arm activity is associated with proinflammatory cytokine production. • SARS-CoV-2 leverages the Ire1α-Xbp1 arm for replication in lung epithelial cells. • The IRE1α-XBP1 arm is activated by Spike proteins from different variants of concern. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a significant global burden of morbidity and mortality, with lung injury being the primary cause of death in affected patients. The pathogenesis of lung injury, however, remains a complex issue. In recent years, the role of the immune system in lung injury has attracted extensive attention worldwide. Despite advancements in our understanding of various lung injury subtypes, significant limitations persist in both prevention and treatment. This review investigates the immunopathogenesis of ALI/ARDS, aiming to elucidate the pathological processes of lung injury mediated by dendritic cells (DCs), natural killer (NK) cells, phagocytes, and neutrophils. Furthermore, the article expounds on the critical contributions of gut microbiota, inflammatory pathways, and cytokine storms in the development of ALI/ARDS. [Display omitted] • Damage to lung tissue caused by immune cell dysfunction. • The ecological stability of intestinal flora is important in protecting lung tissue. • The inflammatory pathway plays a crucial role in regulating and mediating lung injury. • The impact of cytokine storm on lung injury is severe. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, significant toxicities may also be associated with such therapy. Here we report extremely high ferritin in a male patient after such therapy. We present a case of a 52 year old male with a history of B-cell acute lymphoblastic leukemia who received chimeric antigen receptor T-cell (CAR-T) therapy with rapcabtagene autoleucel (carvykti). The patient subsequently developed cytokine release syndrome (CRS) which during its resolution results in a hemophagocytic lymphohistiocytosis (HLH)-like syndrome that fell short of being diagnostic. This syndrome tracked closely with the onset and resolution of immune-effector cell-associated neurotoxicity syndrome (ICANS), with close correlation between the severity of laboratory abnormalities, particularly extremely high ferritin (peak value: 81,540 μg/L), and clinical encephalopathy. Cytokine release syndrome after experimental (CAR) T cell therapy may cause extremely elevated ferritin and hemophagocytic lymphohistiocytosis −like syndrome. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition. M@NP-R treatment significantly ameliorated the clinical and laboratory manifestations of HLH in mouse models, including trilineage cytopenia, hypercytokinemia, organomegaly, hepatorenal dysfunction, and tissue inflammation. Importantly, M@NP-R significantly enhanced the survival of the lethal HLH mice. Altogether, M@NP-R successfully blocked the positive feedback loop between the cytokine storm and macrophage overactivation by depleting extracellular inflammatory cytokines and inhibiting the intracellular JAK/STAT signaling pathway, both of which worked synergistically in HLH treatment. As ruxolitinib has already been extensively used in clinics with favorable safety, and M@NP is biodegradable and highly biocompatible, M@NP-R has good prospects for clinical translation. [ABSTRACT FROM AUTHOR]

• An aminothiazole derivative X22 showed a significant reduction in the levels of inflammatory mediators including NO, TNF-α and IL-6 in RAW 264.7 cells stimulated with LPS. • MEP revealed that the reactive sites are located in CF 3 and NH 2 groups. These particular groups exhibit a strong propensity to engage in hydrogen bonding and dipole-dipole interactions. • Molecular docking studies revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids, Tyr151, Ser60, Gln61, and Arg179. • MD simulation data demonstrated that TNF-alpha exhibits effective binding to the active sites of proteins, resulting in the formation of a stable protein complex. Aminothiazole-based structures, including compounds like anakinra, nitazoxanide, amiphenazole, and tizoxanide, along with cytokine-blocking agents such as tocilizumab and siltuximab are currently under extensive investigation for their potential in managing severe COVID-19 by specifically targeting and inhibiting cytokines responsible for cytokine release syndrome (CRS). These targeted therapies have shown promising results in effectively mitigating the effects of severe COVID-19. Herein, we carried out a biological assessment of a novel aminothiazole-based derivative 5-(phenylthio)-4-(2-(trifluoromethyl) phenyl) thiazol-2-amine (X22) to gauge its potential as an anti-inflammatory agent. Utilizing in vitro assays, which included measuring nitric oxide (NO) inhibition and observing the production of LPS-induced pro-inflammatory cytokines (TNF-α and IL-6) in RAW 264.7 macrophages. Furthermore, the X22 was characterized by experimental FT-IR, NMR, and UV–visible spectral analysis. The optimized molecular geometry and vibrational wave numbers were calculated using the DFT and B3LYP/6–311++ G (d,p) basis set. The vibrational assignments were calculated using VEDA's Potential Energy Distribution (PED) program. 1H and 13C NMR were calculated by the GIAO method. Additionally, compounds HOMO-LUMO and HF interactions were studied. Subsequently, the MEP map was traced to find the reactive sites of X22. In addition, Mulliken population analysis and thermodynamic properties with respect to various temperatures were also calculated. All the theoretical predictions were carried out by using the DFT-B3LYP method at the level of 6–311++ G (d,p). Finally, the molecular docking interactions revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids Tyr 151, Ser60, Gln61, and Arg179. These findings suggest that X22 could be a valuable therapeutic agent for mitigating the progression of severe SARS-CoV-2 infections. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a significant hematological malignancy in the United States, with a high mortality rate and limited treatment options. CAR T-cell therapy, a new and promising treatment, is being investigated for its efficacy and safety in AML. This meta-analysis aims to assess the safety and efficacy of CAR T-cell therapy in AML, considering various subgroups such as study location, study design, prior transplantation status, conditioning regimen, and CAR T-cell source. We conducted a comprehensive literature review across multiple databases, adhering to PRISMA guidelines and focusing on studies concerning CAR T-cell therapy in AML. We included original articles in English and excluded non-original reviews, abstracts, and non-English studies. The risk of bias was assessed using the Cochrane ROBINS-I tool. Statistical analysis involved meta-analysis with Cochrane's Q-test and I² statistic, using both fixed-effect and random-effects models, and assessed for publication bias. Our search yielded studies encompassing 57 AML patients treated with CAR T-cell therapy. The meta-analysis revealed a 48% incidence of complete remission with CAR T-cell therapy, varying significantly across subgroups based on study design, location, prior transplantation, conditioning regimen, and CAR T-cell source. The highest complete remission rates were observed in patients from China, those who had undergone prior hematopoietic cell transplantation, and those treated with fludarabine and cyclophosphamide conditioning regimen. Adverse events included graft-versus-host disease (7%) and cytokine release syndrome (53%). This meta-analysis highlights the potential of CAR T-cell therapy in AML treatment, especially when integrated with certain prior treatments and conditioning regimens. The findings suggest a higher efficacy in patients with previous hematopoietic cell transplantation and specific conditioning regimens. Further large-scale, randomized trials are essential to confirm these findings and establish CAR T-cell therapy as a standard treatment for AML. • Meta-analysis shows 48% AML remission rate with CAR T-cell therapy, varying by study specifics. • High remission in AML patients from China, with prior transplantation and specific regimens. • CAR T-cell therapy in AML linked to 7% graft-vs-host disease, 53% cytokine release syndrome. • Further trials needed to confirm CAR T-cell therapy as a standard AML treatment. [ABSTRACT FROM AUTHOR]