RARE DISEASE
CAR T cell therapy-associated cytokine release syndrome
CAR T cell therapy-associated cytokine release syndrome
CAR T cell therapy-associated cytokine release syndrome
Synonyms: CAR T cell therapy-associated CRS, Chimeric antigen receptor-T cell therapy-associated cytokine release syndrome
Synonyms: CAR T cell therapy-associated CRS, Chimeric antigen receptor-T cell therapy-associated cytokine release syndrome
Synonyms: CAR T cell therapy-associated CRS, Chimeric antigen receptor-T cell therapy-associated cytokine release syndrome
Drug discovery
1
drug
With orphan designation
Overview
CAR T cell therapy-associated cytokine release syndrome (CRS) is a systemic inflammatory response triggered by rapid immune activation post-infusion, characterized by elevated cytokines (e.g., IL-6, IFN-γ) and clinical manifestations ranging from fever to life-threatening capillary leak syndrome. It occurs in 45-90% of patients, typically within days of treatment. Management includes IL-6 blockade (tocilizumab) and corticosteroids, with severity-dependent escalation to critical care [1][2][6][12].
Categories: rare systemic and rheumatological diseases
Research Papers
153 drug discovery papers about CAR T cell therapy-associated cytokine release syndrome, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
153 drug discovery papers about CAR T cell therapy-associated cytokine release syndrome, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-03-04 | Emapalumab in pediatric patients with high-grade cytokine release syndrome associated with CAR T-cell therapy
Background Chimeric antigen receptor T (CAR-T) cell therapy significantly improves the prognosis of a variety of hematological malignancies; however, its broader application in clinical practice is hindered by adverse events, particularly cytokine release syndrome (CRS). Moreover, the selection of treatment strategies for patients with high-grade CRS must be meticulously tailored. Emapalumab, a fully human IgG1 monoclonal antibody targeting IFN-γ, has been proposed to have clinical benefit in CRS. Methods In this retrospective study, we conducted a comprehensive analysis of clinical and laboratory parameters in 38 pediatric patients who failed low-dose glucocorticoids monotherapy, tocilizumab monotherapy or glucocorticoid-tocilizumab combination therapy, following treatment with investigational CAR-T products. Results Emapalumab significantly improved both clinical symptoms and laboratory parameters. The rapid decrease in mean temperature (39.61 vs. 38.38°C, P < 0.001) and levels of inflammatory markers including IL-2 (32.35 vs. 11.94 pg/ml, P < 0.001), IL-10 (222.29 vs. 86.09 pg/ml, P = 0.018), TNF-α (4.17 vs. 2.94 pg/ml, P = 0.032), and IFN-γ (21984.11 vs. 674.87 pg/ml, P < 0.001) indicated the remarkable scavenging efficacy of emapalumab against cytokine storm following CAR-T therapy. Additionally, both mean CAR-T cell counts (549.95 vs. 8.16 cell/μl, P < 0.001) and the ratio of CAR-T to CD3+ (11.3% vs. 36.54%, P < 0.001) in peripheral blood increased significantly, demonstrating that the administration of emapalumab didn’t seem to have a significant negative impact on the proliferation of CAR-T cells. The median EFS and OS were both not reached, with an EFS rate of 76.9% (95%CI, 63.8-92.6) and with an OS rate of 80.1% (95% CI, 67.7-94.6) at 6 months. Throughout the treatment course, no direct evidence of emapalumab-related safety risks was observed. Conclusion Emapalumab seems to serve as an effective salvage therapy for patients experiencing high-grade CRS with inadequate response to low-dose glucocorticoids and/or tocilizumab following CAR-T therapy. These data supported the use of emapalumab in high-grade CRS as well as provide rationale for future prospective studies.
2026-02-27 | CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma in a nonagenarian patient
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the management of relapsed/refractory large B-cell lymphoma. However, evidence in the ultra-elderly population remains scarce. We report a 90-year-old woman with relapsed/refractory diffuse large B-cell lymphoma transformed from follicular lymphoma who received lisocabtagene maraleucel. Despite advanced age, preserved cognition, intact instrumental activities of daily living, and acceptable organ reserve supported her candidacy for CAR T-cell therapy. Cytokine release syndrome (CRS) developed as grade 1 (day 1, 38.0 °C) and grade 2 (day 3, hypoxemia to 6 L/min), which resolved after early tocilizumab and dexamethasone. No immune effector cell-associated neurotoxicity syndrome or infectious complications occurred. Grade 2-4 cytopenia persisted transiently but was managed with supportive care, and she was discharged on day 28. To our knowledge, this represents the first reported case of a nonagenarian Asian patient successfully treated with CAR T-cell therapy, highlighting the feasibility and tolerability of this approach and emphasizing the importance of geriatric assessment and prompt CRS management for safe delivery in the very elderly.
2026-01-01 | Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia
Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ-driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell-associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra-deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesis and neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.
2025-11-28 | Managing Treatment‐Emergent Immune Effector Cell‐Associated Hemophagocytic Lymphohistiocytosis‐Like Syndrome Following CAR‐T Cell Therapy: A Case‐Based Review of the use of Emapalumab
Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR-T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which is characterized by a rare and life-threatening hyperinflammatory response. This paper presents a case of a 56-year-old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR-T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC-HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon-γ blocker. To provide broader context, we conducted a literature review of CAR-T cell-related toxicities, focusing on IEC-HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC-HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR-T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC-HS cases, emapalumab may be used as an effective targeted therapy.
2025-10-30 | IFN-γ–driven skewing towards Th1 over Th17 differentiation underlies CRS and neutropenia in CAR-T therapy
Chimeric antigen receptor T cell (CAR-T) therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT). We utilized IL-2Ra knockout mice to model toxicities with elevated levels of IL-6, IFN-γ, and TNF-α and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils. Both nontumor-bearing and Em-ALL tumor-bearing mice recapitulated the cooccurrence of CRS and neutropenia. IFN-γ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive cooccurrence of CRS and neutropenia in an IFN-γ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN-γ-to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia. We have uncovered a biological basis for ICAHT and provide support for the use of IFN-γ blockade to reduce both CRS and neutropenia.
small molecules
2026-05-05 | Extracorporeal blood purification in the management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome following chimeric antigen receptor T cell therapy: a case report
Chimeric antigen receptor T-cell (CAR-T) therapy is associated with potentially severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We report a case of a 32-year-old man with refractory diffuse large B-cell lymphoma who developed severe ICANS after axicabtagene ciloleucel infusion despite standard treatment with corticosteroids, tocilizumab, anakinra, and supportive therapy. Because of rapid clinical deterioration, extracorporeal blood purification with CytoSorb was initiated. The treatment was followed by rapid neurological and hemodynamic improvement, reduction of inflammatory markers, and transfer from the intensive care unit to the hematology ward. CAR-T cell expansion, monitored by droplet digital PCR, was preserved after cytokine adsorption. This case suggests that extracorporeal blood purification may be a feasible rescue strategy for severe CAR-T-related neurotoxicity without compromising CAR-T cell activity.
2026-03-12 | The Conflicting Role of Myeloid Cells in CAR T-Cell Therapy
Chimeric antigen receptor T (CAR T)-cell therapy is revolutionizing cancer treatment in hematologic malignancies, but challenges related to the tumor microenvironment have hindered CAR T success, especially in solid tumors. Myeloid cells in particular have been implicated in CAR T efficacy. In this review, we discuss the roles of myeloid cells in CAR T-associated toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, along with strategies to treat these toxicities by modulating myeloid cells. The review also explores myeloid cell-mediated suppression or enhancement of CAR T function. Finally, strategies used to target myeloid cells in combination with CAR T-cell therapy will be investigated.
2025-11-02 | High Rate of Cytokine Release Syndrome-Related Coagulopathy with Low Incidence of Bleeding and Thrombosis in Patients Treated with B-Cell Maturation Antigen (BCMA)-Targeted Chimeric Antigen Receptor T-Cells (CAR-T)
Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated substantial efficacy in relapsed and/or refractory multiple myeloma. While toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have been well characterized, the incidence and clinical consequences of the coagulopathy associated with CRS remain underexplored. Methods: We conducted a prospective analysis of 108 adult patients with multiple myeloma or light chain amyloidosis treated with the academic anti-BCMA CAR-T HBI0101 in a single-center trial (NCT04720313). Coagulopathy was evaluated via serial fibrinogen measurements, with hypofibrinogenemia defined as <200 mg/dL and severe coagulopathy as <100 mg/dL. Laboratory markers, tocilizumab and blood product use, and thrombotic and bleeding complications were recorded. Patients received a short (3-day) or extended course of enoxaparin thromboprophylaxis as well as fresh frozen plasma in cases of severe coagulopathy. Results: CRS grades 1-3 occurred in 100 patients (93%). Hypofibrinogenemia was observed in 79 patients (73%), including 20 (19%) with severe coagulopathy. Fibrinogen levels were significantly associated with CRS severity (p < 0.001), number of tocilizumab doses (p < 0.001), peak levels of the inflammation markers LDH (p = 0.001) and ferritin (p = 0.006), and neutropenia (p = 0.33). Five thrombotic events (4.6%) and three minor bleeding events (2.7%) occurred within 3 months post-CAR-T infusion and were not associated with degree of coagulopathy or CRS. No cases of major bleeding or fatal thrombosis occurred. Conclusions: CRS-related coagulopathy is common following BCMA-targeted CAR-T treatment and correlates closely with CRS severity. Despite the high rate of laboratory coagulopathy, thrombosis and bleeding events were infrequent, suggesting the benefit of the prophylactic strategies used.
2025-10-31 | Palindromic rheumatism-like arthritis complicating CAR T-cell therapy
Dear Editor, Chimeric antigen receptor (CAR) T cells have emerged as an effective option for paediatric and adult haematological malignancies, particularly advanced B-cell cancers. In recent years, they have also been evaluated in selected cases of refractory autoimmune disease [1–3]. Engagement of CAR constructs with target-cell surface antigens provokes robust T-cell activation that may precipitate immune-mediated toxicities, mainly cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Other adverse events include immune effector cell–associated haematotoxicity (ICAHT), immune effector cell–associated haemophagocytic lymphohistiocytosis–like syndrome (IEC-HS), cardiotoxicity, metabolic disorders, pulmonary toxicity, coagulation disorders and potential off-target effects on various organs [4]. Beyond these well-recognized events, rheumatological complications apparently related to the procedure are increasingly reported [5, 6]. We describe a case of palindromic rheumatism (PR) arising 4 weeks after CAR T-cell (CAR-T) therapy, successfully managed with HCQ. A 56-year-old woman was diagnosed in September 2023 with diffuse large B-cell lymphoma, stage IIEA, with extensive left humeral involvement and involvement of several locoregional lymph-node territories. First-line treatment comprised R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and local radiotherapy. She relapsed in November 2024, stage IVA, and subsequently received two cycles of R-GEMOX (rituximab, gemcitabine and oxaliplatin). In February 2025, she underwent lymphodepletion with fludarabine and CYC followed by anti-CD19 CAR-T infusion. As a complication, she developed grade II CRS that required treatment with tocilizumab and dexamethasone.
2025-08-23 | Cytokine release syndrome in solid tumors
Cytokine release syndrome (CRS) is a common and potentially severe complication of cancer immunotherapy, including CAR T-cell therapies, bispecific T-cell engagers, and less commonly immune checkpoint inhibitors. Although extensive research has established guidelines for managing CRS in hematological malignancies, there is a growing need to address CRS in the context of solid organ tumors due to differences in tumor microenvironment, immunotherapy indications, and patient population. This review aims to provide an overview of CRS in solid tumors, outlining its pathophysiology, clinical presentation, and current management strategies. The complexities of CRS in solid tumors arise from challenges such as the immunosuppressive nature of the tumor microenvironment and the overlap of tumor-associated antigens with healthy tissues, potentially increasing the risk of severe on-target off-tumor toxicities. The review emphasizes early detection and grading of CRS as essential for patient safety and effective intervention. Management of CRS involves supportive care for mild cases, whereas severe presentations often require targeted therapies like tocilizumab, corticosteroids, and escalation to the intensive care unit for organ support. The decision to rechallenge or withhold immunotherapy requires careful consideration of patient-specific goals and risks. Emerging treatments such as other cytokine inhibitors, plasma exchange, and suicide gene systems are promising avenues for mitigating severe CRS. Future research focuses on refining risk stratification tools, novel therapeutic agents, and evaluating long-term outcomes. A deeper understanding of CRS in solid tumors will enable more personalized treatment approaches, enhancing the safety and efficacy of immunotherapies for this patient population.
cell therapies
2026-05-26 | CAR-T cell therapy in cancer immunotherapy – Biology, clinical successes, and emerging challenges: A review
Cancer immunotherapy has transformed oncology by enabling targeted activation of antitumor immune responses in patients with relapsed or refractory malignancies. Among adoptive cell transfer (ACT) strategies, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a pivotal therapeutic advancement, genetically redirecting T lymphocytes to recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation. This review provides a comprehensive overview of the biological principles, design evolution, manufacturing platforms, clinical applications, resistance mechanisms, toxicities, and future directions of CAR-T cell therapy within cancer immunotherapy. Specifically, we examine the evolution of CAR architecture, spanning from first-generation constructs to advanced armored and fifth-generation platforms. Furthermore, we compare viral and non-viral gene delivery systems and discuss emerging approaches such as in vivo CAR engineering, allogeneic "off-the-shelf" products, logic-gated receptors, safety switches, and alternative immune-cell platforms, including natural killer (NK) cells and macrophages. CAR-T cell therapy has achieved its most profound clinical success in hematological malignancies, particularly in cluster of differentiation 19 (CD19)-positive B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma, reporting durable remission rates of approximately 60-90% in specific clinical contexts. However, broader clinical translation, particularly in solid tumors, remains constrained by challenges such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), antigen escape, tumor heterogeneity, poor trafficking, limited persistence, high manufacturing costs, and the immunosuppressive tumor microenvironment (TME). While next-generation strategies-including clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated editing, lipid nanoparticle (LNP)-based messenger ribonucleic acid (mRNA) delivery, bispecific CARs, and inducible suicide switches-hold promise for improving safety, specificity, scalability, and accessibility, a significant number remain in preclinical or early-phase clinical development. Overall, CAR-T cell therapy represents a transformative "living drug" platform in oncology; however, its broader clinical utility is contingent upon improving durability, reducing toxicity, overcoming solid-tumor barriers, and validating next-generation technologies through robust, long-term clinical studies.
2026-03-27 | Th17-driven CD8+ T cells in hUC-MSC and CAR T-cell dual immunotherapy for superior anti-tumor efficacy
Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for hematological malignancies; however, its efficacy and safety remain challenging, particularly in the context of high tumor burden. High tumor load and substantial residual lesions significantly impair CAR T-cell function and exacerbate cytokine release syndrome (CRS). Here, we report the development of a novel dual cellular immunotherapy in which human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are co-administered with CD19 CAR T-cells. We demonstrated that this combination therapy enhances the anti-tumor efficacy of CD19 CAR T-cells under high tumor burden condition. In xenograft models of high tumor burden B-cell lymphoma, the dual cellular immunotherapy improved survival, mitigated myelosuppression, and preserved CAR T-cell expansion. Transcriptomic analysis of CAR T-cells revealed enrichment of the Th17 pathway in CAR T-cells, while single-cell RNA sequencing showed enhanced, particularly that of NK-like cytotoxic T lymphocytes characteristics which are associated with Th17 differentiation. Furthermore, in a CRS model, hUC-MSCs attenuate CRS severity by suppressing macrophage activity. Collectively, hUC-MSCs significantly enhance the anti-tumor capability of CD19 CAR T-cells under high tumor burden conditions by inducing CD8 + NK-like cytotoxic T lymphocytes through Th17 differentiation, while concurrently mitigating treatment-related side effects. Our study provides a novel therapeutic strategy to improve clinical outcomes in hematological malignancies.
2026-02-03 | Cytokine‐Engineered Chimeric Antigen Receptor‐T Cell Therapy: How to Balance the Efficacy and Toxicity
Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the paradigm in hematological malignancies. However, its efficacy in treating solid tumors remains limited because the immunosuppressive tumor microenvironment (ITME) seriously blocks T cell activation, infiltration, and proliferation. Cytokines, driving potent assisted function by enhanced T cell expansion, persistence, and direct tumor cell killing, have long been acknowledged as promising candidates combined with CAR-T cells to improve treatment outcomes. Despite their preclinical success, significant toxicity occurs in up to one-third of patients induced by powerful immune-mediated cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In these cases, the risk-benefit unbalance is less advantageous for advanced cancer therapies, appealing for a profound understanding of pathophysiological mechanisms of CRS and ICANS, as well as improved management of regulating cytokine production. In this review, we first provide an overview of activation and cytotoxic mechanisms of CAR-T cells. Second, obstacles to CAR-T cells in the ITME are introduced in detail. Third, the advanced design of CAR-T engineered cytokines, coupled with current research progress, is described. Furthermore, pathophysiology and clinical features of CRS and ICANS are described in detail. Lastly, prevention and/or intervention approaches of the two above-mentioned toxicities are emphasized both for developing novel therapeutics and maximizing the benefit of patients.
2026-01-12 | The “cytokine storm” in infection and sepsis: win the battle but lose the war
The cytokine storm, a life-threatening systemic inflammatory syndrome, is the primary driver of multiorgan failure in different clinical situations, including severe infections, autoimmune diseases, chimeric antigen receptor (CAR) T cell immunotherapy for cancer, and genetic syndromes. This review focuses primarily on cytokine storms triggered by severe infections such as viral pneumonia and bacterial sepsis, and explores the underlying mechanisms of cytokine storms and potential therapeutic interventions. Cytokine storms are characterized primarily by the excessive release of proinflammatory cytokines, which are triggered by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and PANoptosis, all of which activate immune signaling cascades. Amplification mechanisms involve positive feedback loops and the failure of negative feedback mechanisms, leading to uncontrolled inflammation. Like a pyrrhic victory, the excessive activation of the immune system eliminated invading pathogens but caused catastrophic damage due to multiple organ dysfunction syndrome (MODS), turning the life-saving response into a life-threatening war. Therapeutic strategies, including cytokine antagonists, Janus kinase (JAK) inhibitors, caspase inhibitors, glucocorticoids, and blood purification therapies, aim to interrupt the self-amplifying cycle of inflammation that propagates organ injury, thereby reducing MODS and mortality. Challenges include optimizing the treatment timing and patient stratification. Future research should focus on combination therapies and personalized medicine based on the heterogeneity of infections and sepsis. Advances in multiomics and targeted therapies provide new hope for managing infections and sepsis.
2026-01-02 | Disulfide-Directed Multicyclic Peptides for Chimeric Antigen Receptors Targeting Solid Tumors
The clinical application of chimeric antigen receptor (CAR) T cell therapy in solid tumors remains limited due to significant safety concerns, particularly "on-target, off-tumor" toxicity and cytokine release syndrome (CRS). Here, we describe a class of CARs that employ disulfide-directed multicyclic peptides (DDMPs) as compact antigen-recognition domains targeting the tumor-associated antigens HER2 and TROP2. DDMP-based CAR T cells exhibited antigen density-dependent cytotoxicity in vitro and in vivo, efficiently eliminating cells with high antigen expression while sparing cells with low antigen levels, thereby mitigating on-target, off-tumor toxicity. In addition, DDMP-based CAR T cells secreted markedly lower levels of pro-inflammatory cytokines upon targeted killing, reducing CRS risk. Mechanistic analyses revealed that this favorable combination of restrained cytokine release and density-gated killing is associated with distinct T cell signaling pathway engagement and reduced cell avidity relative to conventional single-chain variable fragment (scFv)-based CAR T cells. Collectively, these findings establish DDMP-based CARs as a promising framework for engineering safer, yet efficacious, CAR T therapies for solid tumors.
proteins
2026-03-30 | Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management
ABSTRACT: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.
2025-12-26 | Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile. MAIN BODY: This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset. CONCLUSIONS: The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.
2025-09-13 | Impact of Granulocyte Colony Stimulating Factor Use Following CD-19 Chimeric Antigen Receptor T-Cell Therapy
CD-19 chimeric antigen receptor T-cell therapy (CAR-T) has improved outcomes in relapsed/refractory B-cell malignancies but is associated with cytokine-mediated toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicities, and infection. Neutropenia is common following CAR-T and varies in duration. Granulocyte colony-stimulating factor (G-CSF) is used to support neutropenia following CAR-T. However, its use within 14 d post-CAR-T is debated due to concerns it may contribute to CRS and ICANS. Data on the efficacy and safety of G-CSF after CAR-T remain inconclusive with no consensus on its use. The objective of this study was to evaluate the difference in CRS or ICANS development and neutropenia outcomes in patients who received G-CSF within 14 d post-CAR-T versus beyond 14 d. This was a retrospective study evaluating patients ≥ 18 yr who received commercial anti-CD-19 CAR-T therapy from December 1, 2019, through June 30, 2024, at Vanderbilt University Medical Center (VUMC) or Veterans Affairs Tennessee Valley Healthcare System (TVHS). Patients were divided into an early cohort (first G-CSF ≤ d +14) and a late/no cohort (first G-CSF > d +14 or none). Primary outcomes were the incidence of CRS and ICANS. Secondary outcomes included severity of CRS and ICANS, duration of neutropenia, and incidence of early (30 d) and late (90 d) neutropenia. Outcomes were compared across early and late/no G-CSF groups with logistic regression or a proportional odds model as appropriate, with propensity score adjustment for treatment center differences. One hundred fifty-seven patients were included in the analysis (61% early, 39% late/no G-CSF). Most patients were white (81%), male (74%) and received axicabtagene ciloleucel (69%). The most common indication for CAR-T cell therapy was diffuse large B-cell lymphoma (69%) after a median of 3 (IQR 2 to 4) prior lines of therapy. The primary outcome of CRS occurred in 92.7% of the early G-CSF group versus 75.4% of the late/no G-CSF group, though the odds were not significantly different in the adjusted analysis (OR 1.92, 95% CI 0.54 to 6.84, P = 0.317). ICANS occurred in 58.3% of early group versus 41.0% of late/no group patients and was also not statistically significant (OR 1.76, 95% CI 0.71 to 4.36, P = 0.223). Although not statistically significant, higher-grade CRS was more likely in the early group (OR 1.93, 95% CI 0.81-4.57, P=0.136). Grade 3 or 4 ICANS occurred in 24.0% of early and 29.5% of late/no G-CSF patients, with no significant difference. Duration of neutropenia in the first 30 d and incidence of early and late neutropenia were similar between groups. Using G-CSF within 14 d post-CAR-T does not increase the risk of CRS or ICANS compared to use after 14 d or no use. The study found no significant difference in severity of CRS or ICANS, duration of neutropenia, or incidence of early and late neutropenia. This questions the utility of G-CSF for CAR-T patients, as it was not shown to improve neutropenia outcomes.
2025-02-10 | Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma
Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.
2025-01-21 | Management of chimeric antigen receptor T-cell-related toxicity of a patient affected by cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, followed by an intestinal perforation: a case report.
Mantle cell lymphoma is a diverse B-cell lymphoma with varying clinical behaviors. Treating relapsed or refractory mantle cell lymphoma is challenging, with Bruton's tyrosine kinase inhibitors proving effective but not curative. Post-Bruton's tyrosine kinase inhibitor failure, the prognosis remains unfavorable. Brexucabtagene autoleucel, a US Food and Drug and European Medicines Agency-approved anti-CD19 chimeric antigen receptor T-cell therapy, marks a significant breakthrough offering hope in this challenging scenario. This article presents an analysis of the management of short-term chimeric antigen receptor T-cell therapy-associated toxicities, focusing on a specific case of a patient with refractory mantle cell lymphoma. The report underscores the complexities of chimeric antigen receptor T-cell treatment and sheds light on strategies employed to mitigate toxic effects. The case involves a white Caucasian 59-year-old male affected by relapsed mantle cell lymphoma who underwent various treatments, including autologous anti-CD19 chimeric antigen receptor T-cell therapy (brexucabtagene autoleucel). The patient experienced immune effector cell-associated hematotoxicity along with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, necessitating intervention. The management involved a combination of tocilizumab, corticosteroids, and anakinra, which effectively alleviated symptoms. Additionally, the article highlights the patient's case of intestinal perforation following CAR-T therapy. Although there is a correlation between gastrointestinal perforation and interleukin 6 receptor inhibitors, the adverse event was attributed to the patient's preexisting diverticulitis and the immunosuppressive drugs administered leading to cytomegalovirus reactivation. The study emphasizes the evolving landscape of chimeric antigen receptor T-cell therapy and the significance of addressing toxicities associated with this innovative treatment approach. It underscores the value of anakinra as a potential corticosteroid-sparing therapy for immune effector cell-associated neurotoxicity syndrome and raises the need for further research to optimize the management of immune effector cell-associated hematotoxicity and associated complications. The potential preventive use of drugs to mitigate toxicities also warrants exploration, albeit with the current dearth of evidence. In conclusion, this article offers valuable insights into the challenges of managing chimeric antigen receptor T-cell-related toxicities through a detailed case presentation and highlights the significance of adopting multidisciplinary approaches to enhance patient outcomes and safety. Further research is needed to refine strategies and advance the understanding of these complex treatment-associated toxicities.
other
2026-01-27 | In vivo engineering of CAR-T cells: delivery strategies and clinical translation
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies. Nonetheless, its broad clinical adoption is constrained by the logistical, financial, and safety burdens associated with ex vivo cell manufacturing. In vivo CAR-T engineering has emerged as a transformative alternative, enabling the direct reprogramming of endogenous T cells through systemic delivery of CAR-encoding constructs via viral or non-viral vectors. This strategy eliminates the need for leukapheresis, genetic modification, and reinfusion, paving the way for simplified, scalable, and potentially “off-the-shelf” immunotherapies. While challenges such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain shared hurdles, in vivo approaches introduce added complexities, including vector immunogenicity and innate immune sensing. By leveraging RNA-based platforms, in vivo CAR-T engineering is evolving into a programmable immunotherapy modality beyond oncology. At the same time, regulatory frameworks for systemic in vivo reprogramming remain underdeveloped, underscoring the need for harmonized guidelines that balance innovation with patient safety. This review synthesizes progress across major delivery platforms, analyzes key translational and regulatory barriers specific to in vivo approaches, and highlights emerging innovations in vector tropism, immune modulation, and scalable manufacturing. As the field matures, in vivo CAR-T strategies may unlock broader therapeutic applications across oncology and autoimmune disease, redefining the accessibility and precision of cellular immunotherapy.
antibodies
2026-03-04 | Emapalumab in pediatric patients with high-grade cytokine release syndrome associated with CAR T-cell therapy
Background Chimeric antigen receptor T (CAR-T) cell therapy significantly improves the prognosis of a variety of hematological malignancies; however, its broader application in clinical practice is hindered by adverse events, particularly cytokine release syndrome (CRS). Moreover, the selection of treatment strategies for patients with high-grade CRS must be meticulously tailored. Emapalumab, a fully human IgG1 monoclonal antibody targeting IFN-γ, has been proposed to have clinical benefit in CRS. Methods In this retrospective study, we conducted a comprehensive analysis of clinical and laboratory parameters in 38 pediatric patients who failed low-dose glucocorticoids monotherapy, tocilizumab monotherapy or glucocorticoid-tocilizumab combination therapy, following treatment with investigational CAR-T products. Results Emapalumab significantly improved both clinical symptoms and laboratory parameters. The rapid decrease in mean temperature (39.61 vs. 38.38°C, P < 0.001) and levels of inflammatory markers including IL-2 (32.35 vs. 11.94 pg/ml, P < 0.001), IL-10 (222.29 vs. 86.09 pg/ml, P = 0.018), TNF-α (4.17 vs. 2.94 pg/ml, P = 0.032), and IFN-γ (21984.11 vs. 674.87 pg/ml, P < 0.001) indicated the remarkable scavenging efficacy of emapalumab against cytokine storm following CAR-T therapy. Additionally, both mean CAR-T cell counts (549.95 vs. 8.16 cell/μl, P < 0.001) and the ratio of CAR-T to CD3+ (11.3% vs. 36.54%, P < 0.001) in peripheral blood increased significantly, demonstrating that the administration of emapalumab didn’t seem to have a significant negative impact on the proliferation of CAR-T cells. The median EFS and OS were both not reached, with an EFS rate of 76.9% (95%CI, 63.8-92.6) and with an OS rate of 80.1% (95% CI, 67.7-94.6) at 6 months. Throughout the treatment course, no direct evidence of emapalumab-related safety risks was observed. Conclusion Emapalumab seems to serve as an effective salvage therapy for patients experiencing high-grade CRS with inadequate response to low-dose glucocorticoids and/or tocilizumab following CAR-T therapy. These data supported the use of emapalumab in high-grade CRS as well as provide rationale for future prospective studies.
2026-02-27 | CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma in a nonagenarian patient
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the management of relapsed/refractory large B-cell lymphoma. However, evidence in the ultra-elderly population remains scarce. We report a 90-year-old woman with relapsed/refractory diffuse large B-cell lymphoma transformed from follicular lymphoma who received lisocabtagene maraleucel. Despite advanced age, preserved cognition, intact instrumental activities of daily living, and acceptable organ reserve supported her candidacy for CAR T-cell therapy. Cytokine release syndrome (CRS) developed as grade 1 (day 1, 38.0 °C) and grade 2 (day 3, hypoxemia to 6 L/min), which resolved after early tocilizumab and dexamethasone. No immune effector cell-associated neurotoxicity syndrome or infectious complications occurred. Grade 2-4 cytopenia persisted transiently but was managed with supportive care, and she was discharged on day 28. To our knowledge, this represents the first reported case of a nonagenarian Asian patient successfully treated with CAR T-cell therapy, highlighting the feasibility and tolerability of this approach and emphasizing the importance of geriatric assessment and prompt CRS management for safe delivery in the very elderly.
2026-01-01 | Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia
Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ-driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell-associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra-deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesis and neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.
2025-11-28 | Managing Treatment‐Emergent Immune Effector Cell‐Associated Hemophagocytic Lymphohistiocytosis‐Like Syndrome Following CAR‐T Cell Therapy: A Case‐Based Review of the use of Emapalumab
Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR-T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which is characterized by a rare and life-threatening hyperinflammatory response. This paper presents a case of a 56-year-old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR-T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC-HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon-γ blocker. To provide broader context, we conducted a literature review of CAR-T cell-related toxicities, focusing on IEC-HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC-HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR-T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC-HS cases, emapalumab may be used as an effective targeted therapy.
2025-10-30 | IFN-γ–driven skewing towards Th1 over Th17 differentiation underlies CRS and neutropenia in CAR-T therapy
Chimeric antigen receptor T cell (CAR-T) therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT). We utilized IL-2Ra knockout mice to model toxicities with elevated levels of IL-6, IFN-γ, and TNF-α and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils. Both nontumor-bearing and Em-ALL tumor-bearing mice recapitulated the cooccurrence of CRS and neutropenia. IFN-γ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive cooccurrence of CRS and neutropenia in an IFN-γ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFN-γ-to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia. We have uncovered a biological basis for ICAHT and provide support for the use of IFN-γ blockade to reduce both CRS and neutropenia.
small molecules
2026-05-05 | Extracorporeal blood purification in the management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome following chimeric antigen receptor T cell therapy: a case report
Chimeric antigen receptor T-cell (CAR-T) therapy is associated with potentially severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We report a case of a 32-year-old man with refractory diffuse large B-cell lymphoma who developed severe ICANS after axicabtagene ciloleucel infusion despite standard treatment with corticosteroids, tocilizumab, anakinra, and supportive therapy. Because of rapid clinical deterioration, extracorporeal blood purification with CytoSorb was initiated. The treatment was followed by rapid neurological and hemodynamic improvement, reduction of inflammatory markers, and transfer from the intensive care unit to the hematology ward. CAR-T cell expansion, monitored by droplet digital PCR, was preserved after cytokine adsorption. This case suggests that extracorporeal blood purification may be a feasible rescue strategy for severe CAR-T-related neurotoxicity without compromising CAR-T cell activity.
2026-03-12 | The Conflicting Role of Myeloid Cells in CAR T-Cell Therapy
Chimeric antigen receptor T (CAR T)-cell therapy is revolutionizing cancer treatment in hematologic malignancies, but challenges related to the tumor microenvironment have hindered CAR T success, especially in solid tumors. Myeloid cells in particular have been implicated in CAR T efficacy. In this review, we discuss the roles of myeloid cells in CAR T-associated toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, along with strategies to treat these toxicities by modulating myeloid cells. The review also explores myeloid cell-mediated suppression or enhancement of CAR T function. Finally, strategies used to target myeloid cells in combination with CAR T-cell therapy will be investigated.
2025-11-02 | High Rate of Cytokine Release Syndrome-Related Coagulopathy with Low Incidence of Bleeding and Thrombosis in Patients Treated with B-Cell Maturation Antigen (BCMA)-Targeted Chimeric Antigen Receptor T-Cells (CAR-T)
Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated substantial efficacy in relapsed and/or refractory multiple myeloma. While toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have been well characterized, the incidence and clinical consequences of the coagulopathy associated with CRS remain underexplored. Methods: We conducted a prospective analysis of 108 adult patients with multiple myeloma or light chain amyloidosis treated with the academic anti-BCMA CAR-T HBI0101 in a single-center trial (NCT04720313). Coagulopathy was evaluated via serial fibrinogen measurements, with hypofibrinogenemia defined as <200 mg/dL and severe coagulopathy as <100 mg/dL. Laboratory markers, tocilizumab and blood product use, and thrombotic and bleeding complications were recorded. Patients received a short (3-day) or extended course of enoxaparin thromboprophylaxis as well as fresh frozen plasma in cases of severe coagulopathy. Results: CRS grades 1-3 occurred in 100 patients (93%). Hypofibrinogenemia was observed in 79 patients (73%), including 20 (19%) with severe coagulopathy. Fibrinogen levels were significantly associated with CRS severity (p < 0.001), number of tocilizumab doses (p < 0.001), peak levels of the inflammation markers LDH (p = 0.001) and ferritin (p = 0.006), and neutropenia (p = 0.33). Five thrombotic events (4.6%) and three minor bleeding events (2.7%) occurred within 3 months post-CAR-T infusion and were not associated with degree of coagulopathy or CRS. No cases of major bleeding or fatal thrombosis occurred. Conclusions: CRS-related coagulopathy is common following BCMA-targeted CAR-T treatment and correlates closely with CRS severity. Despite the high rate of laboratory coagulopathy, thrombosis and bleeding events were infrequent, suggesting the benefit of the prophylactic strategies used.
2025-10-31 | Palindromic rheumatism-like arthritis complicating CAR T-cell therapy
Dear Editor, Chimeric antigen receptor (CAR) T cells have emerged as an effective option for paediatric and adult haematological malignancies, particularly advanced B-cell cancers. In recent years, they have also been evaluated in selected cases of refractory autoimmune disease [1–3]. Engagement of CAR constructs with target-cell surface antigens provokes robust T-cell activation that may precipitate immune-mediated toxicities, mainly cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Other adverse events include immune effector cell–associated haematotoxicity (ICAHT), immune effector cell–associated haemophagocytic lymphohistiocytosis–like syndrome (IEC-HS), cardiotoxicity, metabolic disorders, pulmonary toxicity, coagulation disorders and potential off-target effects on various organs [4]. Beyond these well-recognized events, rheumatological complications apparently related to the procedure are increasingly reported [5, 6]. We describe a case of palindromic rheumatism (PR) arising 4 weeks after CAR T-cell (CAR-T) therapy, successfully managed with HCQ. A 56-year-old woman was diagnosed in September 2023 with diffuse large B-cell lymphoma, stage IIEA, with extensive left humeral involvement and involvement of several locoregional lymph-node territories. First-line treatment comprised R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and local radiotherapy. She relapsed in November 2024, stage IVA, and subsequently received two cycles of R-GEMOX (rituximab, gemcitabine and oxaliplatin). In February 2025, she underwent lymphodepletion with fludarabine and CYC followed by anti-CD19 CAR-T infusion. As a complication, she developed grade II CRS that required treatment with tocilizumab and dexamethasone.
2025-08-23 | Cytokine release syndrome in solid tumors
Cytokine release syndrome (CRS) is a common and potentially severe complication of cancer immunotherapy, including CAR T-cell therapies, bispecific T-cell engagers, and less commonly immune checkpoint inhibitors. Although extensive research has established guidelines for managing CRS in hematological malignancies, there is a growing need to address CRS in the context of solid organ tumors due to differences in tumor microenvironment, immunotherapy indications, and patient population. This review aims to provide an overview of CRS in solid tumors, outlining its pathophysiology, clinical presentation, and current management strategies. The complexities of CRS in solid tumors arise from challenges such as the immunosuppressive nature of the tumor microenvironment and the overlap of tumor-associated antigens with healthy tissues, potentially increasing the risk of severe on-target off-tumor toxicities. The review emphasizes early detection and grading of CRS as essential for patient safety and effective intervention. Management of CRS involves supportive care for mild cases, whereas severe presentations often require targeted therapies like tocilizumab, corticosteroids, and escalation to the intensive care unit for organ support. The decision to rechallenge or withhold immunotherapy requires careful consideration of patient-specific goals and risks. Emerging treatments such as other cytokine inhibitors, plasma exchange, and suicide gene systems are promising avenues for mitigating severe CRS. Future research focuses on refining risk stratification tools, novel therapeutic agents, and evaluating long-term outcomes. A deeper understanding of CRS in solid tumors will enable more personalized treatment approaches, enhancing the safety and efficacy of immunotherapies for this patient population.
cell therapies
2026-05-26 | CAR-T cell therapy in cancer immunotherapy – Biology, clinical successes, and emerging challenges: A review
Cancer immunotherapy has transformed oncology by enabling targeted activation of antitumor immune responses in patients with relapsed or refractory malignancies. Among adoptive cell transfer (ACT) strategies, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a pivotal therapeutic advancement, genetically redirecting T lymphocytes to recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation. This review provides a comprehensive overview of the biological principles, design evolution, manufacturing platforms, clinical applications, resistance mechanisms, toxicities, and future directions of CAR-T cell therapy within cancer immunotherapy. Specifically, we examine the evolution of CAR architecture, spanning from first-generation constructs to advanced armored and fifth-generation platforms. Furthermore, we compare viral and non-viral gene delivery systems and discuss emerging approaches such as in vivo CAR engineering, allogeneic "off-the-shelf" products, logic-gated receptors, safety switches, and alternative immune-cell platforms, including natural killer (NK) cells and macrophages. CAR-T cell therapy has achieved its most profound clinical success in hematological malignancies, particularly in cluster of differentiation 19 (CD19)-positive B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma, reporting durable remission rates of approximately 60-90% in specific clinical contexts. However, broader clinical translation, particularly in solid tumors, remains constrained by challenges such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), antigen escape, tumor heterogeneity, poor trafficking, limited persistence, high manufacturing costs, and the immunosuppressive tumor microenvironment (TME). While next-generation strategies-including clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated editing, lipid nanoparticle (LNP)-based messenger ribonucleic acid (mRNA) delivery, bispecific CARs, and inducible suicide switches-hold promise for improving safety, specificity, scalability, and accessibility, a significant number remain in preclinical or early-phase clinical development. Overall, CAR-T cell therapy represents a transformative "living drug" platform in oncology; however, its broader clinical utility is contingent upon improving durability, reducing toxicity, overcoming solid-tumor barriers, and validating next-generation technologies through robust, long-term clinical studies.
2026-03-27 | Th17-driven CD8+ T cells in hUC-MSC and CAR T-cell dual immunotherapy for superior anti-tumor efficacy
Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for hematological malignancies; however, its efficacy and safety remain challenging, particularly in the context of high tumor burden. High tumor load and substantial residual lesions significantly impair CAR T-cell function and exacerbate cytokine release syndrome (CRS). Here, we report the development of a novel dual cellular immunotherapy in which human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are co-administered with CD19 CAR T-cells. We demonstrated that this combination therapy enhances the anti-tumor efficacy of CD19 CAR T-cells under high tumor burden condition. In xenograft models of high tumor burden B-cell lymphoma, the dual cellular immunotherapy improved survival, mitigated myelosuppression, and preserved CAR T-cell expansion. Transcriptomic analysis of CAR T-cells revealed enrichment of the Th17 pathway in CAR T-cells, while single-cell RNA sequencing showed enhanced, particularly that of NK-like cytotoxic T lymphocytes characteristics which are associated with Th17 differentiation. Furthermore, in a CRS model, hUC-MSCs attenuate CRS severity by suppressing macrophage activity. Collectively, hUC-MSCs significantly enhance the anti-tumor capability of CD19 CAR T-cells under high tumor burden conditions by inducing CD8 + NK-like cytotoxic T lymphocytes through Th17 differentiation, while concurrently mitigating treatment-related side effects. Our study provides a novel therapeutic strategy to improve clinical outcomes in hematological malignancies.
2026-02-03 | Cytokine‐Engineered Chimeric Antigen Receptor‐T Cell Therapy: How to Balance the Efficacy and Toxicity
Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the paradigm in hematological malignancies. However, its efficacy in treating solid tumors remains limited because the immunosuppressive tumor microenvironment (ITME) seriously blocks T cell activation, infiltration, and proliferation. Cytokines, driving potent assisted function by enhanced T cell expansion, persistence, and direct tumor cell killing, have long been acknowledged as promising candidates combined with CAR-T cells to improve treatment outcomes. Despite their preclinical success, significant toxicity occurs in up to one-third of patients induced by powerful immune-mediated cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In these cases, the risk-benefit unbalance is less advantageous for advanced cancer therapies, appealing for a profound understanding of pathophysiological mechanisms of CRS and ICANS, as well as improved management of regulating cytokine production. In this review, we first provide an overview of activation and cytotoxic mechanisms of CAR-T cells. Second, obstacles to CAR-T cells in the ITME are introduced in detail. Third, the advanced design of CAR-T engineered cytokines, coupled with current research progress, is described. Furthermore, pathophysiology and clinical features of CRS and ICANS are described in detail. Lastly, prevention and/or intervention approaches of the two above-mentioned toxicities are emphasized both for developing novel therapeutics and maximizing the benefit of patients.
2026-01-12 | The “cytokine storm” in infection and sepsis: win the battle but lose the war
The cytokine storm, a life-threatening systemic inflammatory syndrome, is the primary driver of multiorgan failure in different clinical situations, including severe infections, autoimmune diseases, chimeric antigen receptor (CAR) T cell immunotherapy for cancer, and genetic syndromes. This review focuses primarily on cytokine storms triggered by severe infections such as viral pneumonia and bacterial sepsis, and explores the underlying mechanisms of cytokine storms and potential therapeutic interventions. Cytokine storms are characterized primarily by the excessive release of proinflammatory cytokines, which are triggered by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and PANoptosis, all of which activate immune signaling cascades. Amplification mechanisms involve positive feedback loops and the failure of negative feedback mechanisms, leading to uncontrolled inflammation. Like a pyrrhic victory, the excessive activation of the immune system eliminated invading pathogens but caused catastrophic damage due to multiple organ dysfunction syndrome (MODS), turning the life-saving response into a life-threatening war. Therapeutic strategies, including cytokine antagonists, Janus kinase (JAK) inhibitors, caspase inhibitors, glucocorticoids, and blood purification therapies, aim to interrupt the self-amplifying cycle of inflammation that propagates organ injury, thereby reducing MODS and mortality. Challenges include optimizing the treatment timing and patient stratification. Future research should focus on combination therapies and personalized medicine based on the heterogeneity of infections and sepsis. Advances in multiomics and targeted therapies provide new hope for managing infections and sepsis.
2026-01-02 | Disulfide-Directed Multicyclic Peptides for Chimeric Antigen Receptors Targeting Solid Tumors
The clinical application of chimeric antigen receptor (CAR) T cell therapy in solid tumors remains limited due to significant safety concerns, particularly "on-target, off-tumor" toxicity and cytokine release syndrome (CRS). Here, we describe a class of CARs that employ disulfide-directed multicyclic peptides (DDMPs) as compact antigen-recognition domains targeting the tumor-associated antigens HER2 and TROP2. DDMP-based CAR T cells exhibited antigen density-dependent cytotoxicity in vitro and in vivo, efficiently eliminating cells with high antigen expression while sparing cells with low antigen levels, thereby mitigating on-target, off-tumor toxicity. In addition, DDMP-based CAR T cells secreted markedly lower levels of pro-inflammatory cytokines upon targeted killing, reducing CRS risk. Mechanistic analyses revealed that this favorable combination of restrained cytokine release and density-gated killing is associated with distinct T cell signaling pathway engagement and reduced cell avidity relative to conventional single-chain variable fragment (scFv)-based CAR T cells. Collectively, these findings establish DDMP-based CARs as a promising framework for engineering safer, yet efficacious, CAR T therapies for solid tumors.
proteins
2026-03-30 | Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management
ABSTRACT: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.
2025-12-26 | Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile. MAIN BODY: This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset. CONCLUSIONS: The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.
2025-09-13 | Impact of Granulocyte Colony Stimulating Factor Use Following CD-19 Chimeric Antigen Receptor T-Cell Therapy
CD-19 chimeric antigen receptor T-cell therapy (CAR-T) has improved outcomes in relapsed/refractory B-cell malignancies but is associated with cytokine-mediated toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicities, and infection. Neutropenia is common following CAR-T and varies in duration. Granulocyte colony-stimulating factor (G-CSF) is used to support neutropenia following CAR-T. However, its use within 14 d post-CAR-T is debated due to concerns it may contribute to CRS and ICANS. Data on the efficacy and safety of G-CSF after CAR-T remain inconclusive with no consensus on its use. The objective of this study was to evaluate the difference in CRS or ICANS development and neutropenia outcomes in patients who received G-CSF within 14 d post-CAR-T versus beyond 14 d. This was a retrospective study evaluating patients ≥ 18 yr who received commercial anti-CD-19 CAR-T therapy from December 1, 2019, through June 30, 2024, at Vanderbilt University Medical Center (VUMC) or Veterans Affairs Tennessee Valley Healthcare System (TVHS). Patients were divided into an early cohort (first G-CSF ≤ d +14) and a late/no cohort (first G-CSF > d +14 or none). Primary outcomes were the incidence of CRS and ICANS. Secondary outcomes included severity of CRS and ICANS, duration of neutropenia, and incidence of early (30 d) and late (90 d) neutropenia. Outcomes were compared across early and late/no G-CSF groups with logistic regression or a proportional odds model as appropriate, with propensity score adjustment for treatment center differences. One hundred fifty-seven patients were included in the analysis (61% early, 39% late/no G-CSF). Most patients were white (81%), male (74%) and received axicabtagene ciloleucel (69%). The most common indication for CAR-T cell therapy was diffuse large B-cell lymphoma (69%) after a median of 3 (IQR 2 to 4) prior lines of therapy. The primary outcome of CRS occurred in 92.7% of the early G-CSF group versus 75.4% of the late/no G-CSF group, though the odds were not significantly different in the adjusted analysis (OR 1.92, 95% CI 0.54 to 6.84, P = 0.317). ICANS occurred in 58.3% of early group versus 41.0% of late/no group patients and was also not statistically significant (OR 1.76, 95% CI 0.71 to 4.36, P = 0.223). Although not statistically significant, higher-grade CRS was more likely in the early group (OR 1.93, 95% CI 0.81-4.57, P=0.136). Grade 3 or 4 ICANS occurred in 24.0% of early and 29.5% of late/no G-CSF patients, with no significant difference. Duration of neutropenia in the first 30 d and incidence of early and late neutropenia were similar between groups. Using G-CSF within 14 d post-CAR-T does not increase the risk of CRS or ICANS compared to use after 14 d or no use. The study found no significant difference in severity of CRS or ICANS, duration of neutropenia, or incidence of early and late neutropenia. This questions the utility of G-CSF for CAR-T patients, as it was not shown to improve neutropenia outcomes.
2025-02-10 | Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma
Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.
2025-01-21 | Management of chimeric antigen receptor T-cell-related toxicity of a patient affected by cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, followed by an intestinal perforation: a case report.
Mantle cell lymphoma is a diverse B-cell lymphoma with varying clinical behaviors. Treating relapsed or refractory mantle cell lymphoma is challenging, with Bruton's tyrosine kinase inhibitors proving effective but not curative. Post-Bruton's tyrosine kinase inhibitor failure, the prognosis remains unfavorable. Brexucabtagene autoleucel, a US Food and Drug and European Medicines Agency-approved anti-CD19 chimeric antigen receptor T-cell therapy, marks a significant breakthrough offering hope in this challenging scenario. This article presents an analysis of the management of short-term chimeric antigen receptor T-cell therapy-associated toxicities, focusing on a specific case of a patient with refractory mantle cell lymphoma. The report underscores the complexities of chimeric antigen receptor T-cell treatment and sheds light on strategies employed to mitigate toxic effects. The case involves a white Caucasian 59-year-old male affected by relapsed mantle cell lymphoma who underwent various treatments, including autologous anti-CD19 chimeric antigen receptor T-cell therapy (brexucabtagene autoleucel). The patient experienced immune effector cell-associated hematotoxicity along with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, necessitating intervention. The management involved a combination of tocilizumab, corticosteroids, and anakinra, which effectively alleviated symptoms. Additionally, the article highlights the patient's case of intestinal perforation following CAR-T therapy. Although there is a correlation between gastrointestinal perforation and interleukin 6 receptor inhibitors, the adverse event was attributed to the patient's preexisting diverticulitis and the immunosuppressive drugs administered leading to cytomegalovirus reactivation. The study emphasizes the evolving landscape of chimeric antigen receptor T-cell therapy and the significance of addressing toxicities associated with this innovative treatment approach. It underscores the value of anakinra as a potential corticosteroid-sparing therapy for immune effector cell-associated neurotoxicity syndrome and raises the need for further research to optimize the management of immune effector cell-associated hematotoxicity and associated complications. The potential preventive use of drugs to mitigate toxicities also warrants exploration, albeit with the current dearth of evidence. In conclusion, this article offers valuable insights into the challenges of managing chimeric antigen receptor T-cell-related toxicities through a detailed case presentation and highlights the significance of adopting multidisciplinary approaches to enhance patient outcomes and safety. Further research is needed to refine strategies and advance the understanding of these complex treatment-associated toxicities.
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2026-01-27 | In vivo engineering of CAR-T cells: delivery strategies and clinical translation
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies. Nonetheless, its broad clinical adoption is constrained by the logistical, financial, and safety burdens associated with ex vivo cell manufacturing. In vivo CAR-T engineering has emerged as a transformative alternative, enabling the direct reprogramming of endogenous T cells through systemic delivery of CAR-encoding constructs via viral or non-viral vectors. This strategy eliminates the need for leukapheresis, genetic modification, and reinfusion, paving the way for simplified, scalable, and potentially “off-the-shelf” immunotherapies. While challenges such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain shared hurdles, in vivo approaches introduce added complexities, including vector immunogenicity and innate immune sensing. By leveraging RNA-based platforms, in vivo CAR-T engineering is evolving into a programmable immunotherapy modality beyond oncology. At the same time, regulatory frameworks for systemic in vivo reprogramming remain underdeveloped, underscoring the need for harmonized guidelines that balance innovation with patient safety. This review synthesizes progress across major delivery platforms, analyzes key translational and regulatory barriers specific to in vivo approaches, and highlights emerging innovations in vector tropism, immune modulation, and scalable manufacturing. As the field matures, in vivo CAR-T strategies may unlock broader therapeutic applications across oncology and autoimmune disease, redefining the accessibility and precision of cellular immunotherapy.
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Drug Discovery Landscape
1 orphan drug designation for CAR T cell therapy-associated cytokine release syndrome, including 1 approved therapy.
1 orphan drug designation for CAR T cell therapy-associated cytokine release syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
tocilizumab [Actemra] | antibodies | FDA | 2017-08-01 | 2017-08-30 | Genentech Inc., a member of the Roche Group |
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