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Background: Glofitamab is a bispecific antibody with promise for treating relapsed/refractory B‐cell lymphoma according to a phase 1/2 clinical trial. This study examined its real‐world effectiveness. Methods: This was an investigator‐initiated, multicenter retrospective study including 34 patients who had relapsed/refractory B‐cell lymphomas after at least three prior lines of therapy and received glofitamab monotherapy in a compassionate use program in Taiwan between January 2021 and October 2022. Results: At a median follow‐up of 15.9 months, 56% of patients responded to glofitamab and 23% achieved complete remission. Response to the previous line of therapy significantly correlated with response to glofitamab (p =.020). Most responses were durable; only five out of the 19 responders had documented disease recurrence at the data cutoff date. The estimated progression‐free survival (PFS) was 3.2 months, and the estimated 1‐year PFS was 33% for the entire cohort. PFS was better for responders than nonresponders (median PFS, 16.9 vs. 1.8 months; 1‐year PFS, 60% vs. 0%). Forty‐three cytokine release syndrome (CRS) events were observed, three of which were grade 3; all were manageable without glofitamab discontinuation. No immune effector cell–associated neurotoxicity was reported. Among seven hepatitis B virus (HBV) carriers (six had antiviral prophylaxis) and 14 patients with remote HBV (four had antiviral prophylaxis), no HBV reactivation was observed. Conclusions: In this real‐world cohort, glofitamab exhibited effectiveness comparable to trial results without excessive CRS or new safety issues. With appropriate prophylaxis, glofitamab‐treated patients with chronic or remote HBV infection are unlikely to experience virus reactivation. [ABSTRACT FROM AUTHOR]

Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B‐cell lymphoma (DLBCL‐RT) face a dismal prognosis. A 51‐year‐old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL‐RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T‐cell treatment. [ABSTRACT FROM AUTHOR]

Hydrocephalus is one of the most common brain disorders and a life‐long incurable condition. An empirical "one‐size‐fits‐all" approach of cerebrospinal fluid (CSF) shunting remains the mainstay of hydrocephalus treatment and effective pharmacotherapy options are currently lacking. Macrophage‐mediated ChP inflammation and CSF hypersecretion have recently been identified as a significant discovery in the pathogenesis of hydrocephalus. In this study, a pioneering DNA nano‐drug (TSOs) is developed by modifying S2 ssDNA and S4 ssDNA with SPAK ASO and OSR1 ASO in tetrahedral framework nucleic acids (tFNAs) and synthesis via a one‐pot annealing procedure. This construct can significantly knockdown the expression of SPAK and OSR1, along with their downstream ion channel proteins in ChP epithelial cells, thereby leading to a decrease in CSF secretion. Moreover, these findings indicate that TSOs effectively inhibit the M0 to M1 phenotypic switch of ChP macrophages via the MAPK pathways, thus mitigating the cytokine storm. In in vivo post‐hemorrhagic hydrocephalus (PHH) models, TSOs significantly reduce CSF secretion rates, alleviate ChP inflammation, and prevent the onset of hydrocephalus. These compelling results highlight the potential of TSOs as a promising therapeutic option for managing hydrocephalus, with significant applications in the future. [ABSTRACT FROM AUTHOR]

Immunotherapies have revolutionized cancer treatment. These treatments rely on immune cell activation in tumours, which limits the number of patients that respond. Inflammatory molecules, like lipopolysaccharides (LPS), can activate innate immune cells, which convert tumour microenvironments from cold to hot, and increase therapeutic efficacy. However, systemic delivery of lipopolysaccharides (LPS) can induce cytokine storm. In this work, we developed immune‐controlling Salmonella (ICS) that only produce LPS in tumours after colonization and systemic clearance. We tuned the expression of msbB, which controls production of immunogenic LPS, by optimizing its ribosomal binding sites and protein degradation tags. This genetic system induced a controllable inflammatory response and increased dendritic cell cross‐presentation in vitro. The strong off state did not induce TNFα production and prevented adverse events when injected into mice. The accumulation of ICS in tumours after intravenous injection focused immune responses specifically to tumours. Tumour‐specific expression of msbB increased infiltration of immune cells, activated monocytes and neutrophils, increased tumour levels of IL‐6, and activated CD8 T cells in draining lymph nodes. These immune responses reduced tumour growth and increased mouse survival. By increasing the efficacy of bacterial anti‐cancer therapy, localized production of LPS could provide increased options to patients with immune‐resistant cancers. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high‐risk r/r DLBCL with one prior line of therapy. The successful development of CAR T‐cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B‐cell lymphoma subtypes. However, CAR T‐cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T‐cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR‐T cell therapy for B‐cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are utilized in a variety of clinical settings for the management of patients with metastatic non‐small cell lung cancer (mNSCLC). While any organ may be subject to immune‐related adverse events (irAEs) as a consequence of ICI therapy, hematological irAEs are uncommon. We describe a scenario involving a patient with oncogene‐addicted mNSCLC who experienced the rare, life‐threatening complication of hemophagocytic lymphohistiocytosis (HLH) and cytokine release syndrome following the receipt of the IMPower150 regimen (carboplatin/paclitaxel/atezolizumab/bevacizumab) after progression on initial tyrosine kinase inhibitor therapy. Malignancy‐associated HLH, while previously described, is more typically associated with hematological rather than solid cancers and has only very recently been reported among patients receiving ICIs. While identification of hemophagocytosis on bone marrow examination is pathognomonic, this feature is not essential for confirming a diagnosis of HLH. Prompt recognition of suspicious laboratory and clinical features by medical oncologists and engagement with other relevant disciplines is hence critical to ensure optimal management of the condition. [ABSTRACT FROM AUTHOR]

Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ‐67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first‐in‐human, open‐label, phase I, dose‐escalation/dose‐expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ‐67571244 was administered intravenously or subcutaneously using step‐up dosing until ≥1 discontinuation condition was met. Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose‐escalation cohorts (n = 68) and before starting dose‐expansion. Overall, 11 (16.2%) patients experienced ≥1 dose‐limiting toxicity; all experienced ≥1 treatment‐emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ‐67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion‐related reactions, and elevated liver function tests. A prolonged step‐up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T‐cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ‐67571244 efficacy was not achieved, thus MTD and RP2D were not determined. [ABSTRACT FROM AUTHOR]

Summary: Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin‐6 (IL‐6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD‐TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD‐IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD‐not otherwise specified (iMCD‐NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD‐TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion‐resistant thrombocytopenia, similar to what is observed with immune‐mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD‐IPL were associated with elevated IL‐6 and declined following anti‐IL‐6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD‐TAFRO patients whereas IL‐6 drives thrombocytosis in iMCD‐IPL, and these mechanisms likely contribute to disease pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]

Background: Blinatumomab early‐line treatment in B‐cell precursor acute lymphoblastic leukemia (B‐ALL) might improve clinical outcomes. Methods: We conducted a retrospective real‐world cohort analysis in 20 newly diagnosed B‐ALL patients who received reduced‐dose chemotherapy (idarubicin, vindesine, and dexamethasone) for 1–3 weeks, followed by blinatumomab for 1–4 weeks as an induction therapy. Results: At the end of the induction therapy, a complete remission rate of 100% was achieved; 17 (85%) patients were minimal residual disease (MRD) negative (<1 × 10−4). Adverse events (AEs) were reported in 12 (60%) patients—43.8% were grade 1–2 and 56.2% were grade 3–4. No incidence of neurotoxicity or grade ≥3 cytokine release syndrome was reported. Conclusions: Blinatumomab demonstrated a significant improvement in clinical outcomes in patients with newly diagnosed B‐ALL irrespective of their poor‐risk factor status and the pretreatment blast burden. [ABSTRACT FROM AUTHOR]

A wearable sensor capable of directly detecting cytokines in external secretions external to the human body is pivotal for gauging the intensity of the immune response and circumventing inflammatory storms, a significant clinical concern. The detection of low‐concentration cytokines is often hampered due to interference from impurities in secretions. Addressing this challenge, a wearable detection system is developed by integrating a Janus membrane with water auto‐collection/filtering capabilities, and aptamer‐modified graphene field‐effect transistor sensors, enabling the detection of low‐concentration cytokines in undiluted sweat samples. The Janus membrane can automatically filter external secretions and transport them to the sensor surface, effectively eliminating impurity interference and enhancing the sensor's detection capabilities. The device can sensitively detect cytokines (such as TNF‐α, a marker for inflammation and cancer) in undiluted sweat, with a detection range spanning 0.5 to 500 pM, and a detection limit reaching 0.31 pM. The ultra‐flexibility of the sensor is also verified, maintaining stable electrical properties even after enduring up to 50 extreme deformations. These findings indicate that the wearable detection system has the potential to realize low‐concentration cytokines monitoring in the sweat of inflammatory patients, to assist the healthcare system in controlling the body's immune status. [ABSTRACT FROM AUTHOR]

We propose a model‐based, semi‐mechanistic dose‐finding (SDF) design for phase I oncology trials that incorporates pharmacokinetic/pharmacodynamic (PK/PD) information when modeling the dose‐toxicity relationship. This design is motivated by a phase Ib/II clinical trial of anti‐CD20/CD3 T cell therapy in non‐Hodgkin lymphoma patients; it extends a recently proposed SDF model framework by incorporating measurements of a PD biomarker relevant to the primary dose‐limiting toxicity (DLT). We propose joint Bayesian modeling of the PK, PD, and DLT outcomes. Our extensive simulation studies show that on average the proposed design outperforms some common phase I trial designs, including modified toxicity probability interval (mTPI) and Bayesian optimal interval (BOIN) designs, the continual reassessment method (CRM), as well as an SDF design assuming a latent PD biomarker (SDF‐woPD), in terms of the percentage of correct selection of maximum tolerated dose (MTD) and average number of patients allocated to MTD, under a variety of dose‐toxicity scenarios. When the working PK model and the class of link function between the cumulative PD effect and DLT probability is correctly specified, the proposed design also yields better estimated dose‐toxicity curves than CRM and SDF‐woPD. Our sensitivity analyses suggest that the design's performance is reasonably robust to prior specification for the parameter in the link function, as well as misspecification of the PK model and class of the link function. [ABSTRACT FROM AUTHOR]

Introduction: Although anti‐CD19 chimeric antigen receptor (CAR) T cell therapy was approved as a very effective salvage strategy in relapsed/refractory (R/R) B cell lymphoma, the experience in R/R gastrointestinal (GI) lymphoma is still insufficient. Methods: We summarized the efficacy and side effects of anti‐CD19 CAR T‐cell therapy in 12 patients with R/R GI lymphoma. Based on literature, the R/R GI lymphoma patients were divided into subgroups with different characteristics: Bulky/No bulky disease, Gastric/Gastrointestinal involvement, Gastrointestinal/Combined extra‐gastrointestinal lesions, Ulcer/Lumps or nodules type, With/without gastrointestinal bleeding. Results: The objective response rate (ORR) was 66.67% in these 12 patients. The ORR was 83.33% in no bulky disease group, 80.00% in gastric involvement group, 100.00% in ulcer type group, and 80.00% in no gastrointestinal bleeding group. The CR rate was 33.33% in these 12 patients. The CR was 50.0% in no bulky disease group, 60.00% in gastric involvement group, and 80.00% in ulcer type group. The PFS and OS rate of the 12 patients at 6 months after infusion were 54.55% and 58.33%, respectively. The overall survival (OS) at 6 months was higher in no bulky disease group. There was no difference of the OS or the progression free survival (PFS) at 6 months between the other groups. The mean peak of CAR‐T cells and Cytokine Release Syndrome (CRS) grade were higher in gastrointestinal lesions group. The mean peak of IFN‐γ and CRS grade were higher in gastrointestinal bleeding group. Four out of six patients in group of gastrointestinal lesions group were patient with high tumor burden. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding. Conclusions: The ORR and CR of high tumor load, gastrointestinal involvement, lumps or nodules type and gastrointestinal bleeding group were lower. The CRS grade was higher in gastrointestinal lesions group and in gastrointestinal bleeding group. Patients with gastrointestinal involvement only were at higher risk for gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Despite being a new promising tool for cancer therapy, intravenous delivery of oncolytic viruses (OVs) is greatly limited by poor tumor targeting, rapid clearance in the blood, severe organ toxicity, and cytokine release syndrome. Herein, a simple and efficient strategy of erythrocyte‐leveraged oncolytic virotherapy (ELeOVt) is reported, which for the first time assembled OVs on the surface of erythrocytes with up to near 100% efficiency and allowed targeted delivery of OVs to the lung after intravenous injection to achieve excellent treatment of pulmonary metastases while greatly improving the biocompatibility of OVs as a drug. Polyethyleneimine (PEI) as a bridge to assemble OVs on erythrocytes also played an important role in promoting the transfection of OVs. It is found that ELeOVt approach significantly prolonged the circulation time of OVs and increased the OVs distribution in the lung by more than tenfold, thereby significantly improving the treatment of lung metastases while reducing organ and systemic toxicity. Taken together, these findings suggest that the ELeOVt provides a biocompatible, efficient, and widely available approach to empower OVs to combat lung metastasis. [ABSTRACT FROM AUTHOR]

Nonhuman primates are widely used in transplantation research as preclinical xeno- or allo-transplantation models. Rabbit anti-thymoglobulin (ATG) is often used for T-cell depletion as an immunosuppressant. T-cell depletion can cause a secondary cytokine storm syndrome that can be minimized/prevented by a prophylactic administration of systemic corticosteroids and antihistamines. We report a case of death due to CSS in a cynomolgus monkey with follicular hyperplasia-induced systemic lymphadenopathy after ATG administration. A 6-year-old female cynomolgus monkey was rendered diabetic and then transplanted with a genetically modified porcine pancreatic islets (PPI) (50 000 IEQ/kg) through the portal vein 22 days later without immunosuppressant. Because graft function was not comparable, we planned re-transplantation of PPI. For re-transplantation of the PPI, we performed an intravenous (IV) ATG infusion for inductive immunosuppression. The monkey died 3 h and 30 min after ATG administration despite cardiopulmonary resuscitation. Systemic lymphadenopathy was observed on submandibular, axillary, inguinal, foregut, colic, and hilar lymph nodes, and splenomegaly was also observed on necropsy. Histopathologic examination of the lymph node revealed follicular hyperplasia. The IL-6 level was higher after ATG infusion compared to before ATG infusion (before vs. after ATG infusion; 14.9 vs. >5000 pg/mL). The death of the cynomolgus monkey was caused by severe CSS because of apoptosis of B cells in the systemic lymph nodes caused by the ATG administration. A thorough physical examination of palpable lymph nodes and pre-ATG sonographic or computed tomographic screening could have identified lymphadenopathy, potentially preventing its infusion and reducing mortality risk. [ABSTRACT FROM AUTHOR]

Summary: Varnimcabtagene autoleucel (var‐cel) is an academic anti‐CD19 chimeric antigen receptor (CAR) product used for the treatment of non‐Hodgkin lymphoma (NHL) in the CART19‐BE‐01 trial. Here we report updated outcomes of patients with NHL treated with var‐cel. B‐cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty‐five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3‐year duration of response was 56%. The 3‐year progression‐free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression‐free survival. The 3‐year incidence of B‐cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var‐cel was manageable, while B‐cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583. [ABSTRACT FROM AUTHOR]

Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Objectives: We aim to analyze the predictive value of thromboelastography on bleeding severity of patients with chimeric antigen receptor (CAR)‐T cell therapy. Methods: A total of 80 patients with refractory/relapsed hematological malignancy were enrolled and divided into two groups: the severe bleeding group and the non‐severe bleeding group. The thromboelastography data was collected on the day of CAR‐T infusion and the 3rd, 7th, 10th, 13th, 17th, and 20th day after CAR‐T cell infusion. Results: The patients of the severe bleeding group had lower platelet (p <.007), maximum amplitude (p =.002), coagulation index (p =.005), and longer coagulation time (p =.019). Increasing trend in reaction time and coagulation time and decreasing trend in Alpha, maximum amplitude, and coagulation index on Days 0–10, opposite on Days 10–20. Univariate logistic regression analysis and multivariable logistic regression analysis showed maximum amplitude on the 3rd day after CAR‐T cell infusion (MA3) (OR = 0.9; 95% CI = 0.84–0.95; p <.001) and cytokine release syndrome grade (OR = 2.57; 95% CI = 1.35–5.32; p =.006) were significantly associated with high bleeding severity. Conclusions: Thromboelastography was considered to be a good predictor of bleeding severity. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 57-year-old female patient with metastasized uveal melanoma who experienced sepsis-like cytokine release syndrome (CRS) after receiving tebentafusp (tebe), a bispecific antibody used to treat this type of cancer. CRS is a common adverse event associated with T-cell-engaging immunotherapeutic drugs like tebe. The patient exhibited symptoms such as hypotension, tachycardia, and fever after the first administration of tebe, and subsequent doses resulted in severe hypotension and tachycardia that required intensive care. The patient's condition stabilized with treatment, but tebe was discontinued due to the severity of the CRS. The article highlights the need for further research to identify biomarkers that can distinguish sepsis-like CRS from an infection. [Extracted from the article]

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B‐cell maturation antigen (BCMA) is predominantly expressed in B‐lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLITM) is the first T‐cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T‐cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step‐up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure‐response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple‐exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications. [ABSTRACT FROM AUTHOR]

Autonomic dysfunction is a clinical hallmark of infection caused by SARS‐CoV‐2, but the underlying mechanisms are unknown. The vagus nerve inflammatory reflex is an important, well‐characterized mechanism for the reflexive suppression of cytokine storm, and its experimental or clinical impairment facilitates the onset and progression of hyperinflammation. Recent pathological evidence from COVID‐19 victims reveals viral infection and inflammation in the vagus nerve and associated nuclei in the medulla oblongata. Although it has been suggested that vagus nerve inflammation in these patients mediates dysregulated respiration, whether it also contributes to dysfunction of the vagus nerve inflammatory reflex has not been addressed. Because lethality and tissue injury in acute COVID‐19 are characterized by cytokine storm, it is plausible to consider evidence that impairment of the inflammatory reflex may contribute to overproduction of cytokines and resultant hyperinflammatory pathogenesis. Accordingly, here the authors discuss the inflammatory reflex, the consequences of its dysfunction in COVID‐19, and whether there are opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Summary: Glioma, the predominant form of central nervous system (CNS) malignancies, presents a significant challenge due to its high prevalence and low 5‐year survival rate. The efficacy of current treatment methods is limited by the presence of the blood–brain barrier, the immunosuppressive microenvironment, and other factors. Immunotherapy has emerged as a promising approach, as it can overcome the blood–brain barrier. A tumor's immune privilege, which is induced by an immunosuppressive environment, constricts immunotherapy's clinical impact in glioma. Pyroptosis, a programmed cell death mechanism facilitated by gasdermins, plays a significant role in the management of glioma. Its ability to initiate and regulate tumor occurrence, progression, and metastasis is well‐established. However, it is crucial to note that uncontrolled or excessive cell death can result in tissue damage, acute inflammation, and cytokine release syndrome, thereby potentially promoting tumor advancement or recurrence. This paper aims to elucidate the molecular pathways involved in pyroptosis and subsequently discuss its induction in cancer therapy. In addition, the current treatment methods of glioma and the use of pyroptosis in these treatments are introduced. It is hoped to provide more ideas for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Summary: Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer. Given the impact of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and PANoptosis activation, and outlines the multifaceted roles of PANoptosis in diseases together with a potential for therapeutic targeting. We also discuss important concepts and pressing issues for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is crucial for identifying novel therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]

While cytokine release syndrome and immune effector cell‐associated neurotoxicity syndrome are well‐recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR‐T cell therapy expands to new disease indications and the number of long‐term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR‐T cell therapy, including late‐onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long‐term survivorship care of the CAR‐T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effectiveness of donor‐derived chimeric antigen receptor T (CAR‐T) cells in the treatment of relapsed cases after allogeneic hematopoietic stem cell transplantation (allo‐HSCT), and whether donor‐derived peripheral blood stem cells (PBSCs) have a therapeutic effect on pancytopenia after CAR‐T cell therapy. Methods: We analyzed data from five adults with B‐cell acute lymphoblastic leukemia (ALL) who had relapse after allo‐HSCT and received donor‐derived CAR‐T cell therapy and donor‐derived PBSCs to promote hematopoietic recovery. Results: All patients had negative minimal residual disease after CAR‐T therapy, grade 1–2 cytokine release syndrome, and developed grade 4 hematologic toxicity. During the pancytopenia stage after CAR‐T cell therapy, donor‐derived PBSCs were transfused without graft‐versus‐host disease (GVHD) prophylaxis. Four patients had grade I–II acute GVHD (aGVHD). After corticosteroid treatment, aGVHD resolved and hematopoiesis was restored. Although steroids in combination with etanercept and ruxolitinib relieved symptoms in one patient with grade IV aGVHD, complete hematopoietic recovery was not achieved, and the patient died due to severe infection. Conclusions: Donor‐derived CAR‐T cell therapy is safe and effective in patients with relapsed/refractory ALL after allo‐HSCT. Donor‐derived PBSCs infusion could achieve hematopoietic recovery with controllable aGVHD in patients with persistent pancytopenia. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) exist throughout our bodies. We recently revealed the important role of intracardiac EVs induced by myocardial ischemia/reperfusion on cardiac injury and dysfunction. However, the role of EVs isolated from normal tissues remains unclear. Here we found that EVs, derived from murine heart, lung, liver and kidney have similar effects on macrophages and regulate the inflammation, chemotaxis, and phagocytosis of macrophages. Interestingly, EV‐treated macrophages showed LPS resistance with reduced expressions of inflammatory cytokines and enhanced phagocytic activity. Furthermore, we demonstrated that the protein content in EVs contributed to the activation of inflammation, while the RNA component mainly limited the excessive inflammatory response of macrophages to LPS. The enrichment of miRNAs, including miR‐148a‐3p, miR‐1a‐3p and miR‐143‐3p was confirmed in tissue EVs. These EV‐enriched miRNAs contributed to the inflammation remission in LPS induced macrophages through multiple pathways, including STAT3, P65 and SAPK/JNK. Moreover, administration of both EVs and EV‐educated macrophages attenuated septic injury and cytokine storm in murine CLP models. Taken together, the present study disclosed that EVs from normal tissues can orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis. Therefore, tissue derived EVs or their derivatives may serve as potential therapeutic strategies in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Objective: Chimeric antigen receptor T‐cell (CAR‐T) therapy is an emerging treatment for refractory hematologic malignancy. Unplanned ED presentations following CAR‐T present the increasing need for an integrated model of care that allows for the early recognition of its specific complications. Methods: This is a prospective observational study at a tertiary centre. CAR‐T patients (n = 17) were universally enrolled into a study registry by treating providers. These patients were flagged by investigators to trigger a pop‐up notification CAR‐T information warning at ED triage. Medical records were reviewed 90 days for unplanned presentations, complications and patient‐oriented outcomes. Results: Patients receiving CAR‐T frequently encountered toxicity within 7 days of therapy. This was typically mild and occurred in an inpatient setting. Medical record review revealed five unplanned ED presentations (that were recognised as post CAR‐T) and not directly attributable to specific toxicities. Conclusion: If CAR‐T therapy is to be used more widely especially in an outpatient model of care, a standardised ED model of care for recognition of specific complications is needed. [ABSTRACT FROM AUTHOR]

Summary: CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector cell‐associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T‐cell therapy in children with pre‐existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies. [ABSTRACT FROM AUTHOR]

Idecabtagene vicleucel (ide‐cel; bb2121) is a B‐cell maturation antigen–directed chimeric antigen receptor (CAR) T cell therapy approved for treatment of patients with heavily pretreated relapsed and refractory multiple myeloma. This analysis evaluated exposure–response (ER) relationships of ide‐cel with key efficacy end points and safety events. Ide‐cel exposure data were available from 127 patients treated at target doses of 150, 300, or 450 × 106 CAR+ T cells from the phase II KarMMa study (NCT03361748). Key exposure metrics, including area under the curve of the transgene level from 0 to 28 days and maximum transgene level, were calculated using noncompartmental methods. Logistic regression models, using both linear and maximum response function of exposure on the logit scale, were evaluated to quantify observed ER trends, and modified by including statistically significant individual covariates in a stepwise regression analysis. There was wide overlap of exposures across the target doses. ER relationships were observed for the overall and complete response rates, with higher response rates associated with higher exposures. Model‐based evaluations identified female sex and baseline serum monoclonal protein less than or equal to 10 g/L as predictive of a higher objective response rate and a higher complete response rate, respectively. ER relationships were observed for safety events of cytokine release syndrome requiring tocilizumab or corticosteroids. The established ER models were used to quantify the ide‐cel dose–response, which showed a positive benefit–risk assessment for the range of ide‐cel exposures associated with the target dose range of 150–450 × 106 CAR+ T cells. [ABSTRACT FROM AUTHOR]

Bispecific antibodies exhibit proven clinical benefit, and many bispecifics are currently in clinical development for oncology. Cytokine release syndrome (CRS) is a common clinical adverse effect observed following CD3‐based bispecific dosing. However, the pathophysiology of CRS is not fully understood, and no computational model mechanistically describing clinical cytokine dynamics following bispecific dosing in solid tumors exists. Here, a quantitative systems pharmacology (QSP) model describing peripheral clinical cytokine dynamics following bispecific dosing in solid tumors is presented. Using tebentafusp as a case study, a CD3‐bispecific approved for uveal melanoma, the model successfully captures the dynamics of five cytokines. The QSP model was shown to predict observed phenomena, such as cytokine maximum concentration suppression using step‐up dosing regimens and the importance of on‐target off‐tumor binding toward CRS and toxicity. Furthermore, the QSP model provides rationale for these biological phenomena based on dynamics of immune cell activation and desensitization in tumors and healthy tissues. Overall, the QSP model structure presented here serves as a basis to infer cytokine dynamics for other CD3‐based bispecifics or tumor types by altering model parameters to capture the scenario of interest, supporting applications including dose selection, candidate nomination, and disease area selection. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)‐T‐cell therapies have revolutionized the management of acute lymphoblastic leukemia, non‐Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and long‐term "on‐target off‐tumor" effects. Methods: All of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non‐relapse mortality after CAR‐T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post‐CAR‐T‐cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B‐cell maturation antigen (BCMA) CAR‐T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post‐infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion. Results: Bacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR‐T‐cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination. Conclusion: Risk stratification tools are available and may help distinguish between infectious and non‐infectious causes of fever post‐infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied. [ABSTRACT FROM AUTHOR]

Cellular therapies provide a curative‐intent option for patients with relapsedand refractory lymphomas. Current options including high dose chemotherapyfollowed by autologous or allogeneic hematopoietic stem cell transplantation or CD19 chimericantigen receptor T‐cell (CART) therapy. The indication varies according to lymphoma sub‐type and line oftherapy. The sequencing of these therapies and their use in second‐line orlater settings to manage these diseases is undergoing significant changes, withCD19 CAR T becoming a preferred option for relapsed aggressive B‐cell lymphoma.The mechanism of both therapies causes significant yet distinctlymphodepletion, infectious, and inflammatory toxicities. The resulting patternand timing of immune reconstitution helps guide risk‐mitigating strategies,revaccination, and infectious prophylaxis. In this review, we discuss theindication, efficacy, toxicity and immune reconstitution of autologoushematopoietic stem cell transplantation and CAR T therapy for use in thetreatment of lymphoma. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T (CAR‐T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non‐Hodgkin's B‐cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR‐T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR‐T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post‐treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara‐C, Melphalan [BEAM] auto‐haematopoetic stem cell transplant [HSCT]). Methods: Clinical notes of patients with lymphoma who underwent either CAR‐T therapy or BEAM auto‐HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post‐treatment. Results: In total, 129 adults with lymphoma (n = 88 CAR‐T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR‐T, −5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR‐T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR‐T therapy, were moderately positively associated with weight loss. Conclusions: Weight loss, percentage weight loss and NIS were significantly reduced in CAR‐T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss. Key points/Highlights: Our findings suggest approximately one quarter of adults receiving chimeric antigen receptor T (CAR‐T) therapy are malnourished at the time of commencing treatmentCAR‐T therapy is associated with significantly less weight loss and nutrition impact symptoms (nausea, vomiting, diarrhoea, mucositis) than autologous haematopoetic stem cell transplant (BEAM [carmustine/BCNU, Etoposide, cytarabine/Ara‐C, Melphalan] auto‐ haematopoetic stem cell transplant).Neurotoxicity in CAR‐T treatment is associated with significant weight loss and should trigger a dietitian referral. [ABSTRACT FROM AUTHOR]

Scavenging excessively secreted cytokines from plasma is vital for treating cytokine storm syndrome (CSS). Therefore, appropriate adsorbent materials are highly desired for efficient and selectively capturing the plasma cytokines. For this purpose, injectable porous silicon particles (PSPs) are designed as scavenging adsorbents. The fabricated PSP features high porosity for large pore volume and high specific surface area. Polyethylene glycol is coated on the outer surface of PSP for a longer body circulation time, while antibodies are immobilized on the interior surface of PSP for the specific recognition of targeting biomacromolecules. The resultant injectable scavengers demonstrate satisfactory performance for sequestering tumor necrosis factor (TNF) or TNF receptor (TNFR) in serum and in vivo. The salient biocompatibility of the preparing scavenger is demonstrated through simulative hemoperfusion experiments and in vivo toxicology tests. Importantly, the scavengers are injected into mice like a drug to rapidly remove blood‐circulating endogenous TNFR. These features together with its facile fabrication present the silicon‐based porous particles as candidates in clinical application for relieving the infection‐induced CSS. [ABSTRACT FROM AUTHOR]

Background: The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR‐T) cells in the management of acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR‐T‐cell persistence are the leading causes of progressive disease following single‐antigen targeting, we evaluated CD22/CD19 dual‐targeting CAR‐T‐cell therapy efficacy and safety in relapsed/refractory B‐cell malignancies. Methods: The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B‐cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19‐dual‐targeting CAR‐T‐cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random‐effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Results: Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1‐year proportions of overall survival (OS) and progression‐free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1‐year OS and 1‐year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual‐targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19‐CAR‐T cells and third‐generation CAR‐T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment‐related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Conclusions: Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies. This meta‐analysis demonstrates very high responses by using dual‐targeting CAR‐T therapy with a tolerable safety profile in treating R/R B‐cell hematologic malignancies.Although further studies are warranted, these findings may help immunologists and clinicians design proper CAR structure and/or combine with important target therapies to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

People living with HIV have a higher risk of developing lymphoma. Outcomes for people living with HIV with relapsed or refractory (r/r) lymphoma remain poor. For this group of patients, chimeric antigen receptor (CAR) T‐cell therapy represents a new successful treatment strategy. However, people living with HIV were not included in pivotal trials, so data are limited to case reports. We searched the PubMed and Ovid technologies databases for literature until 1 November 2022 using the terms 'HIV and CAR‐T', 'HIV and lymphoma' and 'HIV and CAR‐T and lymphoma'. Six cases with sufficient information were included in the review. The mean CD4+ T‐cell count before CAR T‐cell therapy was 221 cells/μL (range 52–629). The viral load was below the limit of detection in four patients. All patients had diffuse large B‐cell lymphoma (DLBCL) and were treated with gamma‐retroviral‐based axicabtagene ciloleucel. Four patients developed cytokine‐release syndrome (CRS) grade 2 or less or immune effector‐cell‐associated neurotoxicity syndrome (ICANs) grade 3–4. Four of six patients responded to CAR T‐cell therapy (three complete remissions, one partial remission). In summary, there are no clinical reasons to restrict the use of CAR T‐cell therapy in people living with HIV with r/r DLBCL. According to the current data, CAR T‐cell therapy was safe and effective. In people who meet the standard criteria for CAR T‐cell therapy, this treatment approach could significantly improve the unmet need for more effective treatment options for people living with HIV with r/r lymphoma. [ABSTRACT FROM AUTHOR]

Dexamethasone (DEX) given at a dose of 6 mg once‐daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID‐19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti‐inflammatory effects in COVID‐19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed‐effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID‐19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL‐6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL‐6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti‐inflammatory compounds as well as drug combinations in the treatment of cytokine storms. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chimeric antigen receptor (CAR) T‐cell therapy is potentially associated with treatment‐related toxicities mainly consisting of cytokine release syndrome (CRS) and immune‐effector cell‐associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B‐cell lymphoma patients treated with CAR‐T. Methods: Twenty‐one refractory DLCBLs underwent whole‐body and brain [18F]‐fluorodeoxyglucose (FDG) PET before and 30 days after treatment with CAR‐T. Five patients did not develop inflammatory‐related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post‐CAR‐T brain FDG‐PET were compared with a local controls dataset to identify hypometabolic patterns both at single‐patient and group levels (p <.05 after correction for family‐wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG‐PET and compared between patients' subgroups (t‐test). Results: ICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p <.003 FWE‐corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p <.002 FWE‐corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p <.002 FWE‐corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p <.02). Conclusions: Patients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine‐induced inflammation. [ABSTRACT FROM AUTHOR]

Background: Influenza virus (IV) is a leading cause of respiratory tract infections, eliciting responses from key innate immune cells such as Macrophages (MQs), Neutrophils, and Dendritic Cells (DCs). These cells employ diverse mechanisms to combat IV, with Inflammasomes playing a pivotal role in viral infection control. Cellular death mechanisms, including Pyroptosis, Apoptosis, and Necroptosis (collectively called PANoptosis), significantly contribute to the innate immune response. Methods: In this updated review, we delve into the intricate relationship between PANoptosis and Inflammasomes within innate immune cells (MQs, Neutrophils, and DCs) during IV infections. We explore the strategies employed by IV to evade these immune defenses and the consequences of unchecked PANoptosis and inflammasome activation, including the potential development of severe complications such as cytokine storms and tissue damage. Results: Our analysis underscores the interplay between PANoptosis and Inflammasomes as a critical aspect of the innate immune response against IV. We provide insights into IV's various mechanisms to subvert these immune pathways and highlight the importance of understanding these interactions to develop effective antiviral medications. Conclusion: A comprehensive understanding of the dynamic interactions between PANoptosis, Inflammasomes, and IV is essential for advancing our knowledge of innate immune responses to viral infections. This knowledge will be invaluable in developing targeted antiviral therapies to combat IV and mitigate potential complications, including cytokine storms and tissue damage. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is a severe and life-threatening toxicity typically reported in chimeric antigen receptor T cell therapy and is rarely reported in immune checkpoint inhibitor (ICI) therapy. This study reports the case of a 75-year-old Japanese woman who received nivolumab plus ipilimumab therapy for the postoperative recurrence of non-small cell lung cancer. She was admitted to our hospital with fever, hypotension, hepatic disorder, and thrombocytopenia. We observed slight skin rashes on her neck on admission, which spread rapidly across her body within a few days. We diagnosed CRS complicated by severe rashes. CRS symptoms were resolved with corticosteroid therapy, and did not recur thereafter. CRS is a rare, but important, immune-related adverse event associated with ICI therapy. [ABSTRACT FROM AUTHOR]

The agonistic action of several immunomodulatory monoclonal antibodies (mAbs) requires both target antigen binding and clustering of this mAb:target complex by the Fcs interacting with Fcγ receptors (FcγRs), in particular FcγRIIb, on neighboring bystander cells. Fc mutations were made in the immunoglobulin G4 (IgG4)‐based TGN1412 anti‐CD28 mAb to define the role of FcγR interactions in its "super‐agonist" activity. The dual mutation, IgG4‐ED269,270AA, ablated interaction with all human FcγRs and agonistic action was consequentially lost, confirming the FcγR dependence on the action of TGN1412. The IgG4 lower hinge region (F234L235G236G237) was modified by L235E mutation (F234E235G236G237), a mutation commonly used to ablate FcγR binding, including in approved therapeutic mAbs. However, rather than ablating all FcγR binding, IgG4‐L235E conferred specific binding to FcγRIIb, the inhibitory Fc receptor. Furthermore, in combination with the core hinge‐stabilizing mutation (IgG4‐S228P, L235E), this mutation increased affinity for FcγRIIb compared with wild‐type IgG4. In addition to having FcγRIIb specificity, these engineered TGN1412 antibodies retained their super‐agonistic ability, demonstrating that CD28‐ and FcγRIIb‐specific binding are together sufficient for agonistic function. The FcγRIIb‐specific nature of IgG4‐L235E has utility for mAb‐mediated immune agonism therapies that are dependent on FcγRIIb interaction and of anti‐inflammatory mAbs in allergy and autoimmunity that harness FcγRIIb inhibitory signaling. [ABSTRACT FROM AUTHOR]

Summary: In high‐risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T‐cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T‐cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post‐transplant relapsed acute leukaemia who received T‐replete, HLA‐mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre‐transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T‐cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7–13 (median 1.73 × 109/L vs. 0.1 × 109/L; p < 0.0001). Expanded T‐cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon‐gamma production. All patients developed grade 1–3 cytokine release syndrome (CRS) with elevated serum IL‐6 and interferon‐gamma. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [ABSTRACT FROM AUTHOR]

The ongoing pandemic of COVID‐19 is intrinsically a systemic inflammatory disorder; hence, those patients suffering an underlying chronic inflammatory disease such as diabetes mellitus are at high risk of severe complications. Preventing or suppressing the inflammatory responses are of importance in diabetic patients. Sodium‐glucose cotransporters‐2 inhibitors (SGLT2i) are a newly introduced anti‐diabetic drugs that have hypoglycemic effects through the urinary excretion of glucose. They also have an anti‐inflammatory potential in diabetes patients, in addition to improving glycemic control, and while there is no direct data available in diabetic patients with COVID‐19 disease, there is evidence that suggests that SGLT2i can reduce systemic inflammation and diminish the cytokine storm effect via several cellular mechanisms. In the current review, our aim was to classify and describe the molecular and cellular pathways by which SGLT2i have anti‐inflammatory effects in diabetic patients with COVID‐19 disease. [ABSTRACT FROM AUTHOR]

Summary: The use of CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy for relapsed/refractory solid organ transplantation (SOT)‐related post‐transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT‐associated PTLD. Among 22 relapsed/refractory SOT‐PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre‐CAR‐T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR‐T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell‐associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR‐T. The two‐year progression‐free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post‐CAR‐T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR‐T therapy in relapsed/refractory SOT‐related PTLD appeared similar to pivotal CAR‐T data, including approximately one‐third of patients achieving sustained remission. [ABSTRACT FROM AUTHOR]

Background: Teclistamab, a B‐cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC‐1 study. Cytokine release syndrome (CRS), a known manifestation of T‐cell redirection, was observed in 119 of 165 patients (72.1%). Methods: Patients received once‐weekly teclistamab 1.5 mg/kg subcutaneously after two step‐up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. Results: Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. Conclusions: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T‐cell–engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. Plain language summary: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC‐1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation.Most CRS occurred during the step‐up schedule, requiring vigilance during treatment initiation.Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step‐up schedule or administering the next teclistamab dose, to avoid exacerbating CRS.Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab.No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity. In the MajesTEC‐1 study of the B‐cell maturation antigen × CD3 bispecific antibody teclistamab, cytokine release syndrome (CRS) occurred in 72.1% of heavily pretreated patients with relapsed or refractory multiple myeloma. Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 or 2 and manageable; tocilizumab reduced the incidence of subsequent CRS in patients who received it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. [ABSTRACT FROM AUTHOR]

Summary: There are a diverse range of haematological malignancies with varying clinical presentations and prognoses. Patients with haematological malignancy may require admission to critical care at the time of diagnosis or due to treatment related effects and complications. Although the prognosis for such patients requiring critical care has improved, there remain uncertainties in optimal clinical management. Identification of patients who will benefit from critical care admission is challenging and selective involvement of palliative care may help to reduce unnecessary and non‐beneficial treatments. While patients with haematological malignancy can present a challenge to critical care physicians, good outcomes can be achieved. In this narrative review, we provide a brief overview of relevant haematological malignancies for the critical care physician and a summary of recent treatment advances. Subsequently, we focus on critical care management for the patient with haematological malignancy including sepsis; acute respiratory failure; prevention and treatment of tumour lysis syndrome; thrombocytopaenia; and venous thromboembolism. We also discuss immunotherapeutic‐specific related complications and their management, including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome associated with chimeric antigen receptor T‐cell therapy. While the management of haematological malignancies is highly specialised and increasingly centralised, acutely unwell patients often present to their local hospital with complications requiring critical care expertise. The aim of this review is to provide a contemporary overview of disease and management principles for non‐specialist critical care teams. [ABSTRACT FROM AUTHOR]

Summary: Large B‐cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi‐cel) or tisagenlecleucel (tisa‐cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa‐cel versus axi‐cel (52% vs. 48%) compared to 20% versus 80% in ASCT‐fit patients; p < 0.0001. The drop‐out rate from approval to infusion was significantly higher in the ASCT‐unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression‐free and overall survival were similar in both cohorts. CAR T was well‐tolerated in ASCT‐unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real‐world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant. [ABSTRACT FROM AUTHOR]

Immuno‐oncology (IO)‐based therapies such as checkpoint inhibitors, bi‐specific antibodies, and CAR‐T‐cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose‐response relationships for both tumor control and CRS‐related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T‐cell engager (BiTE). Using this model, we evaluated tumor burden, T‐cell activation, and cytokine release in response to bispecific T‐cell‐engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD‐scid Il2rgnull mice lacking expression of mouse MHC class I and II (NSG‐MHC‐DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our findings indicate that this PBMC‐engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experiments. The PBMC humanized mouse model described here is a sensitive and reproducible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications. [ABSTRACT FROM AUTHOR]