Medical dilemma: Programmed death 1 blockade (sintilimab) therapy in patients suffering from tumours combined with psoriasis.

Tumour immunotherapy represented by immune checkpoint inhibitors (ICIs) has greatly improved the overall prognosis of patients with malignant tumours, and is regarded as an important breakthrough in the field of medicine in recent years. ICIs have gradually become the core of tumour therapy and are increasingly used in the clinic. In order to achieve early clinical prediction and management of immune-related adverse events (irAEs), it is still necessary to perform further research on the mechanisms, risk factors, and predictors of irAE occurrence in the future. Zhou et al describe the consultation of a patient with advanced gastric cancer combined with chronic plaque psoriasis. This case provides an important reference for the use of programmed cell death protein-1 (PD-1) inhibitors in patients of tumours combined with chronic plaque psoriasis. This case also highlights that screening of high-risk groups for irAEs is critical before applying PD-1 inhibitors to patients with chronic psoriasis combined with tumours. PD-1 inhibitors are new and potent antineoplastic agents that can cause serious immune-related adverse events such as toxic epidermal necrolysis release and psoriasis. Glucocorticosteroids are the first-line agents for irAEs. The incidence of rheumatic irAEs may be higher in reality, which will inevitably become a new challenge for rheumatologists and dermatologists.

DeltaRex-G, tumor targeted retrovector encoding a CCNG1 inhibitor, for CAR-T cell therapy induced cytokine release syndrome.

Cytokine release syndrome is a serious complication of chimeric antigen receptor-T cell therapy and is triggered by excessive secretion of inflammatory cytokines by chimeric T cells which could be fatal. Following an inquiry into the molecular mechanisms orchestrating cytokine release syndrome, we hypothesize that DeltaRex-G, a tumor targeted retrovector encoding a cytocidal CCNG1 inhibitor gene, may be a viable treatment option for corticosteroid-resistant cytokine release syndrome. DeltaRex-G received United States Food and Drug Administration Emergency Use Authorization to treat Covid-19-induced acute respiratory distress syndrome, which is due to hyperactivated immune cells. A brief administration of DeltaRex-G would inhibit a certain proportion of hyperactive chimeric T cells, consequently reducing cytokine release while retaining chimeric T cell efficacy.

SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2.

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

Tarlatamab for Large Cell Neuroendocrine Carcinoma in a Young Adult: A Case Report.

A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3-targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

Salivary gland swelling as a characteristic manifestation of local cytokine release syndrome after anti-CD19 chimeric antigen receptor T cell therapy: A case series.

Cytokine release syndrome (CRS) is the most common adverse event of chimeric antigen receptor T (CAR-T) cell therapy and is usually characterized by systemic symptoms such as fever, hypotension, and hypoxia. However, there have been several recent reports of local CRS characterized by cervical swelling. This localized syndrome can cause life-threatening laryngeal edema and requires early diagnostic treatment. Here we report 3 cases of local CRS where bilateral salivary gland swelling emerged following anti-CD19 CAR-T cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Following tocilizumab treatment for systemic CRS, all patients exhibited cervical swelling. Physical examinations revealed significant swelling of the bilateral submandibular glands, and computed tomography scans showed substantial enlargement of the bilateral parotid and submandibular glands. Immediate treatment with dexamethasone effectively managed the potentially life-threatening laryngeal or pharyngeal edema, thereby preventing severe airway obstruction. This study has demonstrated, for the first time to our knowledge, that salivary gland enlargement is a common finding in local CRS. This observation suggests that physicians should continue to closely monitor the risk of developing cervical edema leading to life-threatening airway obstruction after systemic CRS, even in patients treated with tocilizumab. If salivary gland swelling is observed, it would be better to consider prompt evaluation and dexamethasone administration.

Endothelial Activation and Stress Index Score as a Prognostic Factor of Cytokine Release Syndrome in CAR-T Patients - A Retrospective Analysis of Multiple Myeloma and Large B-Cell Lymphoma Cohorts.

Endothelial Activation and Stress Index (EASIX) has been proposed as a prognostic factor of adverse events or survival in hematological malignancies. Endothelial dysfunction has been associated with complications following stem cell transplantation and chimeric antigen receptor (CAR)-T therapy. This retrospective cohort study evaluated the utility of the EASIX score as a prognostic factor of cytokine release syndrome (CRS) in multiple myeloma/light-chain amyloidosis (MM/AL amyloidosis; N = 69) and large B-cell lymphoma (LBCL) cohorts (N = 65). Occurrence of CRS grade ≥3 was the primary endpoint. For both cohorts, the EASIX and simplified EASIX (s-EASIX) scores were calculated at four different time points before CAR-T infusion to assess its prognostic value. In the MM/AL amyloidosis cohort, neither EASIX nor s-EASIX scores calculated at any time point were associated with the occurrence of CRS grade ≥3. In the LBCL cohort, EASIX and s-EASIX scores measured before lymphodepletion (EASIX-pre and s-EASIX-pre) showed a significant relationship with CRS grade ≥3 (odds ratio [OR] = 1.06 and OR = 1.05, respectively). The cutoff value of 1.835 for EASIX-pre was associated with 4.59-fold increased OR of CRS grade ≥3 (95% confidence interval [CI]: 1.13-21.84), whereas s-EASIX-pre cutoff equaled 2.134 and was associated with 4.13-fold increased OR of CRS grade ≥3 (95% CI: 1.01-17.93). However, after internal validation with bootstrapping, the significance was lost both for the EASIX-pre and s-EASIX-pre cutoff. The presented findings indicate that the EASIX scores fail to predict CRS in MM/amyloidosis CAR-T patients, whereas they can be implemented as CRS grade ≥3 predictors in LBCL CAR-T patients.

Cytokine release syndrome following COVID-19 infection during treatment with nivolumab for cancer of esophagogastric junction carcinoma: a case report and review.

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

Macrophage Activation Syndrome in Coinciding Pandemics of Obesity and COVID-19: Worse than Bad.

Epigenetic changes have long-lasting impacts, which influence the epigenome and are maintained during cell division. Thus, human genome changes have required a very long timescale to become a major contributor to the current obesity pandemic. Whereas bidirectional effects of coronavirus disease 2019 (COVID-19) and obesity pandemics have given the opportunity to explore, how the viral microribonucleic acids (miRNAs) use the human's transcriptional machinery that regulate gene expression at a posttranscriptional level. Obesity and its related comorbidity, type 2 diabetes (T2D), and new-onset diabetes due to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are additional risk factors, which increase the severity of COVID-19 and its related mortality. The higher mortality rate of these patients is dependent on severe cytokine storm, which is the sum of the additional cytokine production by concomitant comorbidities and own cytokine synthesis of COVID-19. Patients with obesity facilitate the SARS-CoV-2 entry to host cell via increasing the host's cell receptor expression and modifying the host cell proteases. After entering the host cells, the SARS-CoV-2 genome directly functions as a messenger ribonucleic acid (mRNA) and encodes a set of nonstructural proteins via processing by the own proteases, main protease (Mpro), and papain-like protease (PLpro) to initiate viral genome replication and transcription. Following viral invasion, SARS-CoV-2 infection reduces insulin secretion via either inducing ß-cell apoptosis or reducing intensity of angiotensin-converting enzyme 2 (ACE2) receptors and leads to new-onset diabetes. Since both T2D and severity of COVID-19 are associated with the increased serum levels of pro-inflammatory cytokines, high glucose levels in T2D aggravate SARS-CoV-2 infection. Elevated neopterin (NPT) value due to persistent interferon gamma (IFN-γ)-mediated monocyte-macrophage activation is an indicator of hyperactivated pro-inflammatory phenotype M1 macrophages. Thus, NPT could be a reliable biomarker for the simultaneously occurring COVID-19-, obesity- and T2D-induced cytokine storm. While host miRNAs attack viral RNAs, viral miRNAs target host transcripts. Eventually, the expression rate and type of miRNAs also are different in COVID-19 patients with different viral loads. It is concluded that specific miRNA signatures in macrophage activation phase may provide an opportunity to become aware of the severity of COVID-19 in patients with obesity and obesity-related T2D.

Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

BACKGROUND: Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). METHODS: We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. RESULTS: Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n = 58) than in the pre-DF era (31% vs. 13%, p = .04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p = .04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p < .01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p = .01) and juvenile myelomonocytic leukemia (OR = 8.98, p = .04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. CONCLUSIONS: Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

From the mechanism of action to clinical management: A review of cardiovascular toxicity in adult treated with CAR-T therapy.

Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications.

Cytokine release syndrome and immune effector cell­associated neurotoxicity syndrome in a melanoma patient treated with adjuvant pembrolizumab.

The emergence of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with solid tumors. However, along with their efficacy, new toxicities related to immune system activation have surfaced, some of which pose life-threatening risks. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are among the serious, albeit rare, immune-related adverse effects (irAEs) observed. Although commonly associated with hematologic malignancies and chimeric antigen receptor T cell therapies, CRS has been reported in patients treated with ICIs, with ICANS being a less documented complication. The present study presents a case report of a 76-year-old patient with resected melanoma who developed clinical symptoms of CRS and ICANS following adjuvant pembrolizumab therapy. The patient presented with neurological symptoms of weakness and encephalopathy with confusion, bradypsychia, dysarthria, tremors and visual hallucinations. Laboratory tests revealed elevated serum levels of tumor necrosis factor-alpha and interleukin-6 along with inflammatory markers, hepatic and renal dysfunction, as well as rapidly progressive normochromic-normocytic anemia. Treatment with corticosteroids led to rapid symptom resolution, albeit with subsequent symptom recurrence after tapering its dose. This case underscores the importance of recognizing and managing irAEs associated with ICIs and highlights the need for vigilant monitoring and individualized therapeutic approaches.

Serum Cytokine Panels in Pediatric Clinical Practice.

BACKGROUND: Cytokines are soluble signaling proteins that regulate inflammation and coordinate immune responses. Serum cytokine assays are increasingly used in medical practice, yet our understanding of cytokines as biomarkers for disease remains limited. OBJECTIVES: We aimed to analyze real-world single center usage of a multiplexed cytokine panel, correlate its results with diagnosis and severity, and explore its utility in pediatric practice. METHODS: A multiplexed cytokine panel, able to return same-day results, was implemented in April 2020 at our institution and its performance was validated for clinical use. Coded patient data were collected using a REDCap database, and correlations between cytokine levels and outcomes of interest were analyzed retrospectively. RESULTS: Cytokine levels correlate with acuity of care, with patients admitted to the pediatric intensive care unit (PICU) having the highest cytokine values. Patients with familial HLH (fHLH) showed prominent peaks in IFNγ, IL-10, and TNF, while patients with sepsis exhibited high IL-6 and IL-8 with relatively modest IFNγ, and cytokine release syndrome (CRS) post-CAR T cell therapy often demonstrated pan-panel positivity at peak levels, with a similar pattern as that of fHLH. A ratio of [IFNγ]+[IL-10]/[IL-6]+[IL-8] levels was able to distinguish fHLH and CRS from severe sepsis. CONCLUSIONS: Cytokine levels correlate with severity of illness and can help differentiate between syndromes that present similarly, including fHLH and CRS compared to sepsis. Cytokine panels can be used as biomarkers to inform diagnosis and management decisions, but significant work remains to dissect complex clinical patterns of disease.

Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy.

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

Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia.

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

Misdiagnosis of severe and atypical oxaliplatin­related hypersensitivity reaction following chemotherapy combined with PD­1 inhibitor: A case report and literature review.

Although the efficacy of treatment strategies for cancer have been improving steadily over the past decade, the adverse event profile following such treatments has also become increasingly complex. The present report described the case of a 67-year-old male patient with gastric stump carcinoma with liver invasion. The patient was treated with oxaliplatin and capecitabine (CAPEOX regimen) chemotherapy, combined with the programmed cell death protein-1 (PD-1) inhibitor tislelizumab. Following treatment, the patient suffered from chills, high fever and facial flushing, followed by shock. Relevant examination results revealed severe multiple organ damage, as well as a significant elevation in IL-6 and procalcitonin (PCT) levels. Initially, the patient was diagnosed with either immune-related adverse events (irAEs) associated with cytokine release syndrome caused by tislelizumab or severe bacterial infection. However, when tislelizumab treatment was stopped and the CAPEOX chemotherapy regimen was reapplied, similar symptoms recurred. Following screening, it was finally determined that severe hypersensitivity reaction (HSR) caused by oxaliplatin was the cause underlying these symptoms. A literature review was then performed, which found that severe oxaliplatin-related HSR is rare, rendering the present case atypical. The present case exhibited no common HSR symptoms, such as cutaneous and respiratory symptoms. However, the patient suffered from serious multiple organ damage, which was misdiagnosed as irAE when oxaliplatin chemotherapy combined with the PD-1 inhibitor was administered. In addition, this apparent severe oxaliplatin-related HSR caused a significant increase in PCT levels, which was misdiagnosed as severe bacterial infection and prevented the use of glucocorticoids. This, in turn, aggravated the damage in this patient.

Safety outcomes of teclistamab accelerated dose escalation.

INTRODUCTION: Teclistamab, a bispecific T-cell engaging antibody targeting B-cell maturation antigen (BCMA), is indicated for the treatment of relapsed or refractory multiple myeloma after at least four lines of therapy. It has boxed warnings for life threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). To mitigate these risks, teclistamab is initiated using step-up doses. This article examines safety event rates following the implementation of a 2-day separation between step-up doses at one institution to streamline patient care. METHODS: This was a retrospective, single-center study encompassing all patients who received teclistamab within a 1-year period. The primary endpoint was the overall incidence of CRS and ICANS. Secondary endpoints included hospital length of stay, hematological toxicities, infection rates, among other adverse events. RESULTS: A total of 27 patients were included in the analysis and stratified into accelerated (days 1,3,5) or standard (days 1,4,7) dosing groups. CRS occurred in 48% (11) of patients for the accelerated dosing and 50% (2) for the standard dosing group. ICANS was seen in 17% (4) of patients in the accelerated dosing group and none in the standard dosing group. Average length of stay in the accelerated dose was 7.6 days versus 9.2 days in the standard dose group. CONCLUSION: Accelerated dose escalation of teclistamab yielded safety event rates comparable to those in the literature. These findings may support outpatient administration for teclistamab. Accelerated dose escalation strategy allowed for the optimization of hospitalization and resources.

Introduction.

The coronavirus disease 2019 (COVID-19) pandemic emerged just months after the publication of the first ever textbook devoted to cytokine storm syndromes (CSSs). The severe disease caused by COVID-19 and the intersection between immune responses and their pathologies played out before the world in media reports, in scientific publications, and through the personal narratives of millions of people's experiences. An entirely new immune-mediated disease, multisystem inflammatory disease in children (MISC), was described. Cytokines played a role in all of these areas, bringing the idea of a cytokine storm squarely to the front and center of the public eye. At the same time, science continued to progress in the lab and in the clinic, thus illuminating our understanding of CSSs both old and new since the publication of the first edition of this book. It was clear that a new edition was needed to keep up with these changes.

Management of Toxicities Associated with BCMA, GPRC5D, and FcRH5-Targeting Bispecific Antibodies in Multiple Myeloma.

PURPOSE OF REVIEW: The introduction of bispecific antibodies is one of the most significant recent advances in the treatment of relapsed/refractory multiple myeloma. This review will summarize the management of the toxicities associated with newly approved T cell-engaging bispecific antibodies and those which may be approved in the near future. RECENT FINDINGS: Numerous trials have shown that bispecific antibodies can be both effective and tolerable when adverse events are properly managed. Cytokine release syndrome and increased infections are observed across all bispecific antibodies. Additional adverse events are target-specific, such as the more severe hypogammaglobulinemia and infections of BCMA bispecific antibodies and the dysgeusia, nail dystrophy, and skin changes of GPRC5D bispecific antibodies. Bispecific antibodies will surely become a mainstay of multiple myeloma therapy given their efficacy and accessibility. Their unique toxicities must be carefully considered and managed to ensure they are utilized safely.

Cytokine release syndrome after CAR T-cell therapy for B-cell acute lymphoblastic leukemia in children and young adolescents: storms make trees take deeper roots.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have revolutionized cancer treatment, showing significant success, including treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Despite their efficacy, cytokine release syndrome (CRS) emerges as a common early adverse effect that can be life threatening in severe cases, resulting from the immune system's targeted activation against tumors. AREAS COVERED: This review concentrates on CRS in children and young adults undergoing CAR T-cell therapy for B-ALL. It explores CRS pathophysiology, clinical presentation, and incidence, emphasizing the importance of a consensus definition and grading to homogenize the treatment according to the severity of symptoms. We will discuss the standard of care treatment of CRS but also novel approaches. We will highlight the importance of managing CRS without compromising the efficacy of immune cell activation against tumors. EXPERT OPINION: As CAR T-cell therapy in pediatric B-ALL become increasingly available and used, optimal management of CRS becomes increasingly important. Early recognition and timely management has improved. Further information will aid us to identify optimal timing of tocilizumab and corticosteroids. Continued bench research coupled with clinical studies and biomarker discovery will allow for valuable insights into CRS pathophysiology and patient and/or cell-targeted treatments.

Regulation of CAR transgene expression to design semiautonomous CAR-T.

Effective transgene expression is critical for genetically engineered cell therapy. Therefore, one of CAR-T cell therapy's critical areas of interest, both in registered products and next-generation approaches is the expression of transgenes. It turns out that various constitutive promoters used in clinical products may influence CAR-T cell antitumor effectiveness and impact the manufacturing process. Furthermore, next-generation CAR-T starts to install remotely controlled inducible promoters or even autonomous expression systems, opening new ways of priming, boosting, and increasing the safety of CAR-T. In this article, a wide range of constitutive and inducible promoters has been grouped and structured, making it possible to compare their pros and cons as well as clinical usage. Finally, logic gates based on Synthetic Notch have been elaborated, demonstrating the coupling of desired external signals with genetically engineered cellular responses.