Cytokine release syndrome in solid tumors

Abstract

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.

Short abstract

The tumor microenvironment alters cytokine kinetics, making cytokine release syndrome in solid organ tumors distinct from hematologic disease. This review distils current evidence on pathophysiology, grading, interleukin‐6–centered therapy, and patient‐specific decisions regarding management.

INTRODUCTION

Over the past decade, cancer immunotherapy has marked a major advance in cancer treatment. This has resulted in incremental improvements in outcomes for patients, particularly in melanoma, lung cancer, renal cell cancer and others. ¹ , ² , ³ Therapies like immune checkpoint inhibitors (ICIs), bispecific T‐cell engaging antibodies (BiTEs), and adoptive cell therapies (ACT), including chimeric antigen receptor (CAR) T‐cells, exemplify this progress. To date, there are few licensed immunotherapeutic strategies for solid organ tumors outside ICIs (see Table 1), however, there is emerging evidence for the utility of BiTEs in small cell lung carcinoma ⁴ and uveal melanoma. ⁵ CAR T‐cell therapy is not yet approved for solid organ tumors, but stage III clinical trials are ongoing (Table 1). ⁷ Despite their clinical success, these therapies can lead to significant toxicities, often driven by immune activation.

TABLE 1.

FDA approvals and emerging indications of immunotherapy for solid organ malignancies associated with the development of CRS.

FDA‐approved agents
Class	Drugs	Diseases	Incidence of CRS (%)	Emerging indications
PD‐1/PD‐L1 inhibitors (ICI)	Pembrolizumab, nivolumab, atezolizumab, durvalumab, cemiplimab	Melanoma, HCC, NSCLC, esophageal, colorectal, gastric, RCC, bladder, breast, cervical	1
LAG‐3 (ICI)	Relatlimab	Melanoma	Unknown	Non–small cell lung cancer, colorectal cancer, urothelial cancer, soft tissue sarcoma, Merkel cell carcinoma
CTLA‐4 Inhibitors (ICI)	Ipilimumab, tremilimumab	Melanoma, HCC, NSCLC, esophageal, colorectal, gastric, RCC	1
DLL‐3 (BiTE)	Tarlatamab 4	Extensive stage small cell lung cancer	51	Limited stage small cell lung cancer
T‐cell receptor gp100 specific (BiTE)	Tebentafusp 5	Uveal melanoma	89	Cutaneous melanoma
Dendritic‐cell vaccine	Sipuleucel T 6	mCRPC	3.5–71.2

Phase 3 studies investigating CAR T in solid tumors
Class	Drugs	Diseases	Incidence of CRS (%)	Clinicaltrials.gov 7
CAR T cells	Anti CEA CAR T cells	Pancreatic cancer	Unknown	NCT04037241
IL‐15 receptor agonist	N‐803	NSCLC, nonmuscle–invasive bladder cancer	90	NCT03022825; NCT03520686

Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CTLA‐4, cytotoxic T lymphocyte antigen‐4; DLL3, delta‐like canonical Notch ligand 3; FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; IL, interleukin; LAG‐3, lymphocyte activation gene 3; mCRPC, Metastatic castration‐resistant prostate cancer; NSCLC, non–small cell lung cancer; PD‐L1, programmed death‐ligand 1; RCC, renal cell carcinoma.

Cytokine release syndrome (CRS) is a potentially life‐threatening complication, occurring more commonly in patients receiving CAR T‐cell therapy and BiTEs. CRS can present as a spectrum from mild to severe, with worsening symptoms such as fever, hypotension, and hypoxia. ⁸ It is a systemic inflammatory response triggered by an excessive immune reaction involving T cells, B cells, natural killer (NK) cells, and macrophages. ⁹ Early recognition and intervention of CRS is crucial to ensure appropriate diagnosis, management, and escalation of care. In the most severe cases, life‐threatening complications such as hypotension, requiring high‐dose vasopressors, and hypoxia, necessitating mechanical ventilation, can arise. Additionally, common laboratory abnormalities in CRS patients include cytopenias, coagulopathies, elevated liver enzymes, and acute kidney injury. ¹⁰

The incidence of CRS in patients receiving CAR T‐cell therapy has been reported to range from 57%–93%. ¹¹ Although CAR T‐cell therapy is predominantly used in hematological malignancies, clinical trials are currently ongoing to investigate efficacy in solid organ tumors. ¹² Case reports have also described CRS occurrence in ICIs, which are commonly used in solid organ malignancies, albeit a less frequent and often underreported adverse effect. ¹³ , ¹⁴ Recent phase 2 and phase 3 clinical trials of newer BiTEs having an incidence as high as 51% and 89%. ⁴ , ¹⁵

Although CRS and its management have been extensively characterized in hematological malignancies, evidence relating to CRS in solid tumors remains scarce. This article explores possible mechanistic and clinical factors that may render CRS in solid tumors analogous or distinct from hematological cases, in anticipation of its expected increase in incidence. Moreover, solid tumors exhibit diverse stromal architectures, vascular perfusion patterns, and tumor‐immune microenvironments that may alter cytokine kinetics and symptom manifestation. Accordingly, this review systematically probes this emerging challenge by organizing the discussion into four principal aims:

1. Explore the pathophysiology of CRS in solid organ tumors.

2. Discuss the clinical presentation and grading of CRS.

3. Discuss the management of CRS with emphasis on solid organ tumors.

4. Explore the challenges of treating CRS in solid organ tumors and the potential future directions of therapy.

PATHOPHYSIOLOGY OF CRS

Cytokines are small‐molecule signaling proteins that regulate immune responses, hematopoiesis, and communication between cells. They also mediate host responses to infections, inflammatory stimuli, and medications. ¹⁶ , ¹⁷ , ¹⁸ CRS was first described in the early 1990s as a complication of the anti–T‐cell antibody, muromonab‐CD3 (OKT3), which was used as an immunotherapy for solid organ transplantation. ¹⁹ , ²⁰ In renal allograft recipients, it was identified that self‐limited, massive cytokine release correlated with the known spontaneously reversible clinical syndrome of fever, headache, and gastrointestinal symptoms experienced with first dose of OKT3. Serum tumor necrosis factor (TNF), interferon‐γ (IFN‐γ), and interleukin (IL)‐2 were transiently elevated during the period of acute symptoms. ¹⁹ The rise in cytokines and clinical symptoms were mitigated in the patients who received concomitant corticosteroids, suggesting an explanation for this common side effect.

As immunotherapies have continued to develop and their use becomes more common, CRS has been described in several antibody‐based therapies such as nivolumab, ²¹ anti‐thymocyte globulin (ATG), ²² rituximab, ²³ obinutuzumab, ²⁴ alemtuzumab, ²⁵ brentuximab, ²⁶ and dacetuzumab. ²⁷ Severe viral infections such as COVID‐19 or influenza can also trigger immune and nonimmune cell stimulation to the extent of CRS, sometimes referred to as a cytokine storm. ²⁸ , ²⁹

Although the precise mechanisms underlying CRS are still being investigated, it is widely understood that, based on data from hematological malignancies, the syndrome is initiated by the binding of BiTEs, CAR T cells, or less commonly ICIs, to their target antigens. The interaction not only activates the intended target cells but also induces activation in bystander immune and nonimmune cells. ¹⁰ , ¹¹ , ³⁰ This activation leads to the extensive release of various proinflammatory cytokines including IL‐6, IL‐1, IL‐5, IL‐10, IFN‐γ, TNF‐α, and transforming growth factors (TGFs) by B‐ and T‐lymphocytes and NK cells. CRS is further amplified through interactions with cellular bystanders, including endothelial cells, monocytes/macrophages, and dendritic cells, which escalate cytokine hypersecretion, worsen symptoms, and contribute to varying degrees of organ damage. ³¹ The key players implicated in the development of CRS include IFN‐γ, IL‐6, endothelial cells, and the tumor microenvironment (TME) in solid tumors.

NK centered platforms—tri‐specific killer engagers, CAR‐NK cells, and NK‐cell engagers—rarely provoke clinically relevant CRS in stark contrast to T‐cell redirecting CAR‐T, BiTE, or checkpoint inhibitors. To date, these data are based on hematological malignancies alone. ³² , ³³ This is likely due to primary NK cells producing very little granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) or IL‐6 on engagement, so the macrophage amplification never starts. ³⁴

IFN‐γ

In the context of T‐cell engagers, CRS is activated by substantial release of IFN‐γ by either activated T cells or the tumor cells themselves, which can cause fever, neurological symptoms, and fatigue. The secreted IFN‐γ then triggers stimulation of other immune cells, notably macrophages. ³⁵ This stimulation of macrophages leads to the production of cytokines such as IL‐6, TNF‐α, and IL‐10. IL‐6 appears to have the most prominent function in CRS and is consistently observed to be elevated in the serum of patients experiencing CRS.^35–37 This has been demonstrated in humanized mouse models where it was shown that human monocytes were a major source of IL‐1 and IL‐6 during CRS.³⁶ Translational research through in vitro assays and single‐cell RNA sequencing supports this, as well as the effectiveness of tocilizumab therapy, an IL‐6 receptor antagonist. ³⁶ , ³⁷ , ³⁸

IL‐6

IL‐6 is a pleiotropic cytokine with both proinflammatory and anti‐inflammatory properties. It is synthesized by a range of cell types, such as T cells, monocytes, macrophages, dendritic cells, mesenchymal cells, and osteoblasts. It plays various roles across different phases of inflammation, initially promoting tissue‐damaging inflammatory responses, subsequently aiding in the resolution of inflammation, and ultimately supporting tissue repair during the later stages. ³⁹ IL‐6 can signal via two different pathways known as classical signaling and trans‐signaling. Classical IL‐6 signaling, which predominantly reduces inflammation, involves the binding of IL‐6 to membrane‐bound IL‐6 receptors (mIL‐6R) on the cell surface. ⁴⁰ The mIL‐6R is not expressed on all cell types; its presence is predominantly limited to hepatocytes, plasma cells, megakaryocytes, and certain leucocytes such as neutrophils, monocytes, and T cells. ⁴¹ However, nearly all cells express gp130, a signal‐transducing component essential for IL‐6 signaling. Cells that only express gp130 can still be activated by IL‐6 through a mechanism known as trans‐signaling. In this process, IL‐6 binds to a soluble form of the IL‐6 receptor (sIL‐6R) in the extracellular environment. The resulting IL‐6/sIL‐6R complex can interact with gp130 on cells lacking mIL‐6R, initiating a proinflammatory signaling cascade seen in CRS. ⁴⁰ , ⁴² IL‐6 plays a significant role in critical aspects of severe CRS that can lead to disseminated intravascular coagulation (DIC), including vascular leakage and the activation of both complement and coagulation pathways. ⁴³ It is suggested that genetic variants in the IL‐6 gene can result in overexpression of IL‐6 via trans‐signaling and thus polymorphisms may predispose patients to CRS. ⁴⁴ , ⁴⁵ This is not yet in clinical use.

Endothelial cells

Activation of endothelial cells is postulated to play a central role in the pathogenesis of severe CRS and potentially provide an explanation for the hallmarks of severe CRS such as capillary leakage, coagulopathy, and hypotension. Endothelial cells are the cells that line the interior surface of blood vessels, forming the thin layer of endothelium. The activation of endothelial cells can result in increased vascular permeability, facilitating the extravasation of plasma proteins and fluids into the interstitial space, which can contribute to hypotension and edema. ⁴⁶ Markers of endothelial activation such as Ang‐2 and von Willebrand factor are frequently raised in the serum of patients with CRS and have been demonstrated to be an important source of IL‐6 in post‐mortem examination of fatal CRS. ⁴⁷ , ⁴⁸ IL‐6 trans‐signaling activates endothelial cells, which express gp130, causing production of additional inflammatory cytokines like IL‐6. The newly produced IL‐6 can further activate endothelial cells, both directly and through the generation of more sIL‐6R. This creates a positive feedback or proinflammatory loop, amplifying the CRS response and potentially leading to excessive inflammation and tissue damage. ⁴⁹ The dysfunction of endothelial cells has been identified as a predictor of prognosis, CRS, and DIC in patients treated with anti‐CD19 CAR T cells. ⁵⁰

Tumor microenvironment

In contrast to liquid malignancies, the solid TME represents a heterogeneous and multifaceted intratumoral structure that contains neoplastic and nonneoplastic cells. ⁵¹ , ⁵² , ⁵³ As a result, CRS in solid tumors may have varied pathophysiology compared to hematological malignancies (Figure 1). As CAR T‐cells typically circulate in the blood after infusion, liquid malignancies can be easily reached but there is difficulty accessing solid tumor cells due to high intratumoral pressure and the dense, abnormal TME. The TME offers immunologic challenges due to immunosuppressive cytokines and suppressor cells, the nature of which may vary by disease site and its histology. ⁵⁴ , ⁵⁵ Myeloid‐derived suppressor cells and regulatory T cells (Tregs) actively suppress the immune response as do cytokines like IL‐10 and TGF‐β that may in turn potentiate CRS severity.

FIGURE 1.

Pathophysiology of cytokine release syndrome in solid organ malignancies.

Tumor endothelial cells differ from their normal counterparts due to the distinct conditions of the TME. Unlike the organized, hierarchical structure of normal vasculature, tumor vessels exhibit irregular and variable density. The endothelial cells often display abnormal morphology, with poor intercellular connections and extended cytoplasmic projections. ⁵⁶ Structural abnormalities in TME vasculature promote fluid and plasma protein extravasation, raising interstitial fluid pressure. Further investigation is required to explore whether this facilitates cytokine transfer between the TME and systemic circulation, potentially amplifying a proinflammatory loop in CRS.

Tumor antigen

Pre‐clinical data supports the theory that tumor antigen density impacts the degree of cytokine release. Majzner and colleagues ⁵⁷ showed that the formation of CAR‐T synapses increases with surface antigen density, and even small changes in signaling motifs can alter the antigen density threshold required for T‐cell activation and cytokine secretion dramatically. Tumor burden and tumor expression (antigen copies per cell) are described as being strongly linked to the release of inflammatory cytokines such as IL‐6, and simulations have shown that the predicted IL‐6 levels vary depending on these factors. ⁵⁸ These data suggest that the characteristics of the tumor—such as antigen density and distribution—are just as important as the engineering of the cell product itself.

Clinical data, however, reveal a more complex reality. High‐density, broadly expressed epithelial antigens can elicit robust CRS even in the context of modest tumor burden when the antigen is not confined to metastatic disease but is abundant across multiple organs. ⁴ , ⁵⁹ , ⁶⁰ Conversely, antigens that are both highly expressed and topographically restricted may mitigate the severity of CRS. For example, Claudin‐18.2 is highly expressed in gastric epithelium but largely absent from other essential tissues, thereby limiting off‐target macrophage activation. In the first‐in‐human trial of CLDN18.2‐CAR‐T cells for gastric and pancreatic cancer, 94% of patients experienced only grade 1–2 CRS, with no grade ≥3 events reported. ⁶¹ This mirrors early hemato‐oncology findings, where patients with low tumor burden exhibited lower cytokine peaks after CD19 CAR‐T therapy than those with bulky disease, highlighting total antigen load as a key driver of toxicity. ⁶² The combination of high antigen load, vital‐organ expression, and a cytokine‐rich TME makes antigen selection a critical lever for modulating CRS in solid tumors. Understanding and quantifying these factors will be essential for replicating the success of cellular immunotherapy in hematologic cancers without reproducing their toxicities.

CLINICAL TRIALS AND THE INCIDENCE OF CRS

Recent clinical trial data (Table 1) shows CRS to be common in BiTEs and CAR T‐cell therapy with incidences ranging from 51% to 90%. The complication is rare in ICIs at approximately 1%. Data is limited on the true incidence of CRS across all solid organ malignancies.

CLINICAL PRESENTATION AND GRADING

Early detection and grading of CRS are crucial for patient safety, timely and appropriate therapeutic interventions, and management. This approach facilitates escalation to critical care when needed and allows for careful monitoring of syndrome progression.

Clinical manifestations

The clinical presentation of CRS can vary from flu‐like symptoms to life‐threatening multiorgan dysfunction (Figure 2).^7–10,47,63 A limitation exists in that the majority of the clinical data and experience is from liquid malignancies. Fever is a hallmark and typically the first clinical sign. Fatigue, myalgia, headache, and chills are often reported in early stages of the illness along with gastrointestinal symptoms such as diarrhea and vomiting. Severe CRS can progress to hypotension and hypoxia such that intensive care and organ supports are required in the form of vasopressors, mechanical ventilation, and renal replacement therapy. Disseminated intravascular coagulation, capillary leak syndrome, liver dysfunction, and acute kidney injury are also recognized complications of the inflammatory process. Neurotoxicity has been described to occur either concurrently or after other features of CRS and may manifest as encephalopathy, delirium, seizures, and other neurological changes. This is now defined as a separate entity of immune effector cell‐associated neurotoxicity syndrome (ICANS) because of its distinct timing, response to intervention, and unclear pathophysiology. ⁸ , ⁶³

FIGURE 2.

Clinical presentation of cytokine release syndrome in solid organ malignancies.

The time‐to‐onset and duration of CRS is variable and can differ depending on the type of immunotherapy. Based on current data, which is hematologic malignancy predominant, CRS can occur within minutes to hours after antibody therapy, ⁹ within days to weeks of adoptive T‐cell therapies coinciding with peak T‐cell expansion, ⁴⁸ and usually within a week to 30 days of ICI therapy. ⁶⁴ Mild CRS tends to resolve within a few days, whereas the severe form may persist for several weeks or longer. ⁶⁵

In addition to sepsis, other differentials should be considered and excluded. These include decompensation of heart failure, thromboembolism, allergic reaction, and tumor progression. Although tumor lysis syndrome is a common oncological emergency in hematological malignancies, it is extremely rare in solid organ tumors but carries a high mortality risk. ⁶⁶ , ⁶⁷

Laboratory testing

CRS is marked by notable changes in numerous laboratory parameters. Although cytokine abnormalities are well‐documented, real‐time cytokine data are rarely accessible in most hospitals or clinical areas, as mentioned in several articles, limiting their utility for timely grading and management. ⁸ , ⁹ , ³¹ , ⁶⁵ Although IL‐6 is involved in the pathophysiology of CRS, its levels do not necessarily correlate with disease severity or response to treatment. ⁶⁸ This is based on translational research through prospective clinical trials to identify predictive biomarkers of CRS in CAR T‐cell therapy for hematological malignancies. ⁶⁸ C‐reactive protein (CRP) is both widely accessible and cost‐effective, initially showing promise as a useful surrogate biomarker for CRS. ⁶⁸ , ⁶⁹ CRP lacks specificity for this syndrome, however, and its variability, along with the delay in its elevation relative to clinical worsening, limits its practical utility in clinical settings. Clinicians must also bear in mind that CRS and sepsis can occur concomitantly, necessitating a low threshold for suspicion of each.

Serum cytokine levels, such INF‐γ, are frequently higher in patients with CRS due to CAR T‐cell therapy than in patients with CRS induced by sepsis, who often have higher levels of circulating IL‐1β, procalcitonin, and other markers of damage to endothelia. Combinations of assays to rule out infection and measure serum cytokines can therefore assist in identifying the trigger for massive cytokine release. ⁷⁰ , ⁷¹ Although some specialized centers may have access to these assays, they are not yet widely used in clinical practice.

Grading

Several other grading systems for CRS had been produced before the current American Society for Transplantation and Cellular Therapy (ASTCT) grading system (Table 2), which was published in 2019. This system grades CRS from 1–5, based on clinical features, and was developed in response to considerable variation in the assessment and grading of toxicities across clinical trials and institutions. This made it challenging to compare product safety and impeded the development of effective management strategies. ⁸ The earlier systems included CTCAE versions 4.0‐5.0, ⁷² , ⁷³ and the Lee, ⁹ Penn, ⁷⁴ MSKCC, ⁷⁵ and CARTOX ⁶³ criteria.

TABLE 2.

ASTCT CRS consensus grading.

CRS parameter	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Fever	Temperature ≥38°C	Temperature ≥38°C	Temperature ≥38°C	Temperature ≥38°C	Death due to CRS
with
Hypotension	None	Not requiring vasopressors	Requiring a vasopressor with or without vasopressin	Requiring multiple vasopressors (excluding vasopressin)
And/or
Hypoxia	None	Requiring low‐flow nasal cannula or blow‐by	Requiring high‐flow nasal cannula, facemask, nonrebreather mask, or Venturi mask	Requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation)

Note: Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading. ⁸

Abbreviations: ASTCT, American Society for Transplantation and Cellular Therapy; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events.

The ASTCT system has been developed based on liquid malignancy data but is currently being used by many clinicians for solid organ malignancies. ⁴ , ⁷⁶ It uses observable clinical parameters, such as fever, hypotension, and hypoxia, to grade CRS, enabling easy implementation across health care settings. Although it recognizes laboratory markers like cytokine levels and CRP, these are excluded from grading due to limited real‐time standardization and availability. To ensure consistent grading, the system provides clear definitions for key symptoms and specifies criteria for CRS resolution, accounting for anti‐cytokine therapies, and requiring all CRS‐related signs and symptoms to fully subside.

Defining resolution of CRS

As per the ASTCT system, patients remain classified as having CRS until all symptoms prompting the diagnosis have resolved, not just fever. Following tocilizumab administration, fever typically subsides within hours, although other CRS symptoms may persist for longer. Fever is required for CRS grading, and cytokine therapies are used only in patients meeting CRS criteria, but the grade can be lowered as hemodynamic stability and oxygen levels improve post‐treatment. Severe CRS is generally considered resolved when fever subsides and the patient no longer requires supplemental oxygen or vasopressor support.

MANAGEMENT

The overarching goal in managing CRS for cancer patients undergoing immunotherapy is to prevent life‐threatening complications while preserving the potential for a favorable antitumor response. Many immune cell therapies for solid tumors, to date, are given in a palliative rather than curative setting. This is likely to change substantially in the coming years. Appropriate and individualized ceilings of care should therefore be established, with patient involvement, at the beginning of immune therapy and reviewed upon recognition of toxicity such as CRS. If infection cannot be ruled out, initiating empiric antibiotic therapy is advised, especially in those with neutropenia. Although current treatment algorithms are largely extrapolated from hematological malignancies, data from more than 200 recipients of immune‐effector cell therapies for solid tumors show that approximately 90% of grade ≥2 CRS episodes resolved following ASTCT‐guided administration of tocilizumab, with or without adjunctive corticosteroids—an efficacy profile that closely parallels outcomes in B‐cell CAR‐T cohorts. ⁷⁶ , ⁷⁷ Clinicians must bear in mind that guidelines for CRS in solid organ malignancies specifically are not currently available.

Supportive care

Grade 1 CRS is managed with supportive care, including close monitoring of organ function and targeted interventions as needed such as resuscitation with intravenous (iv) crystalloid and anti‐pyretics. Early proactive involvement of intensive care and multidisciplinary teams is recommended. Although fluid resuscitation can improve blood pressure, it may worsen edema in the context of impaired cardiac or renal function, so vasopressor support is often required to prevent fluid overload. Grade 2 and higher require further intervention as described below.

Patients with higher grades of CRS (grades 3–4) have been shown to have close to 10 times the likelihood of developing acute kidney injury (AKI) compared to those with milder grades of CRS following CAR T‐cell therapy. ⁷⁸ In that study, most kidney injuries appeared to be due to decreased kidney perfusion and improved with hemodynamic support. Furthermore, the severity of AKI has been found to correlate with the grade of CRS. ⁷⁹ Electrolyte disorders are also an established adverse effect of immune cell therapies, especially in CRS, with hypokalemia, hyponatremia, and hypophosphatemia being most common. ⁶³ , ⁷⁸ , ⁸⁰ Regular monitoring and replacement are advised in a high dependency setting. Serial blood tests should be conducted to monitor for cytopenias or signs of DIC. American Society of Clinical Oncology (ASCO) guidelines, built almost entirely on evidence from hematological malignancies, recommend regular measurement of CRP, ferritin, and cytokines, where available, to help interpret the patient's clinical course and inform future clinical trials. ⁸¹ IL‐6, TNF‐α, and IFN‐γ are the more commonly measured cytokines. Even in centers with in‐house testing, however, results can take more than 24 hours.

IL‐6 receptor antagonists

Tocilizumab is a humanized immunoglobulin G1k monoclonal antibody targeting the human IL‐6 receptor (IL‐6R), which works by preventing IL‐6 from binding to both cell‐associated and soluble IL‐6Rs. This action inhibits both classical and trans‐signaling of IL‐6 with the goal of dampening massive cytokine release. Tocilizumab was approved by the FDA in 2017 for severe or life‐threatening CRS induced by CAR T‐cell therapy in adults and pediatric patients aged 2 years and older. ⁸² Tocilizumab is the first‐line treatment for CRS.^7,83 Current guidelines suggest its use in patients with ASTCT grade 2 CRS and, in certain cases, for those with ASTCT grade 1 CRS. ⁸³ Reassuringly, data have shown that tocilizumab does not impact CAR T‐cell expansion and therefore the risk of reducing efficacy is low. ⁸⁴

For grade 2 CRS and above, or grade 1 CRS persisting for more than 3 days, tocilizumab may be initiated at 8 mg/kg (up to a maximum dose of 800 mg) and can be administered every 8 hours, with a maximum of three doses within a 24‐hour period. It may also be considered for specific organ toxicities, including severe acute kidney or liver injury, heart failure with reduced ejection fraction, or significant electrolyte imbalances. ⁸⁵ However, most patients experiencing severe organ toxicities typically already present with grade 2 or higher CRS. If effective, symptoms typically improve within hours to 2 days of administration. This reflects the rapid bioavailability of tocilizumab for which the maximal serum concentration can be reached within 2 hours. ⁸⁶ Tocilizumab is generally well tolerated with few adverse effects reported in studies evaluating its use in rheumatological conditions. These were predominantly infection, neutropenia, gastrointestinal complaints, rash, and headache. ⁸⁷ , ⁸⁸ It does, however, carry a risk of severe bacterial infections. ⁸⁹ Targeting IL‐6R with tocilizumab has not proven effective for preventing or treating neurotoxicity in ICANS, which may be due to its limited distribution into the central nervous system. ⁹⁰ , ⁹¹

Recent work by Daoudlarian et al. ⁹² has expanded the therapeutic rationale for IL‐6 blockade for ICI–driven hyper‐inflammation. In ICI therapy, corticosteroids are often administered initially for suspected immune‐related adverse events and tocilizumab can be added for irHLH. ⁹³ , ⁹⁴ This contrasts with CRS guidelines that advise tocilizumab first and corticosteroids as second‐line. ⁸ , ⁶⁵ , ⁸² In a biomarker‐directed study of 35 adults who developed hyperinflammatory conditions such as immune‐related hemophagocytic lymphohistiocytosis (irHLH), immune‐related CRS (irCRS), or sepsis during ICI therapy, the investigators used biomarker profiling to identify means of differentiating between these conditions. An additional aim of this study was to retrospectively assess how effectively tocilizumab controlled high‐grade steroid‐refractory irCRS. Ferritin and hepatocyte‐growth factor (HGF) each provided 100% positive and negative predictive value for distinguishing irCRS from irHLH, whereas serum CXCL9 levels identified patients likely to require escalation beyond corticosteroids. Twelve individuals with grade‐3 irCRS refractory to ≥48 hours of high‐dose methylprednisolone received tocilizumab 8 mg/kg. All achieved complete clinical and biochemical remission within 24 hours. No patients relapsed over a median 9‐week follow‐up. Tumor control was preserved, with seven maintaining partial responses and the remainder stable disease at first re‐staging. Beyond corroborating the therapeutic value of IL‐6 blockade, the study underscores how biomarkers such as ferritin, HGF, and CXCL9 can be useful in guiding treatment escalation.

Tocilizumab‐refractory CRS

Corticosteroids are an agreed second‐line therapy for CAR T‐cell–related CRS that is refractory to tocilizumab therapy. Although indications vary slightly among recent guidelines, ⁶⁵ , ⁸¹ , ⁹⁵ , ⁹⁶ ASCO guidelines advise administration of glucocorticoids in patients with grade 3 CRS or higher, or those with grade 2 CRS who have not responded clinically to two iv fluid boluses (dosed at physician’s discretion) and one and two doses of tocilizumab. Dosing depends on grading. For grade 2 CRS, dexamethasone 10 mg iv every 12 hours is advised. For grade 3, dexamethasone 10 mg iv every 6 h with taper on improvement. For grade 4 CRS, it is advised to escalate to methylprednisolone 500 mg iv every 12 h with taper as clinically appropriate. If symptoms remain refractory following glucocorticoid therapy for any grade of CRS, treatment should proceed based on guidelines for the next highest CRS grade. For refractory severe CRS, it is recommended to administer methylprednisolone at 1000 mg iv every 12 hours. ⁸¹ Corticosteroids pose a significant risk of further immunosuppression, carrying an amplified threat of opportunistic bacterial, viral, and fungal infections. ⁹⁷ Other side effects include worsening of edema, insulin resistance leading to hyperglycemia, and neuropsychiatric syndromes. One must also consider the long‐term effects of repeated corticosteroid exposure in cancer patients throughout their disease journey.

Conflicting data exists as to the effect of glucocorticoids on CAR T‐cell efficacy and overall survival. In early studies, patients who were treated for CRS with glucocorticoids demonstrated a decrease in blood CAR T‐cell levels, reduced CAR T‐cell persistence, and more frequent relapses of malignancy. ⁶⁹ , ⁹⁸ , ⁹⁹ Although these findings have not been supported by recent data, ¹⁰⁰ , ¹⁰¹ there is no available analysis for the long‐term effects of glucocorticoids on patients with solid organ tumors who develop CRS. As discussed, BiTEs are often used in solid organ tumors in conjunction with CAR T‐cell therapy which allows targeting to tumors with high specificity. The effects of glucocorticoids on BiTEs are not definitive but in vitro studies suggest a potential amelioration of T‐cell exhaustion (i.e., improving persistence). ¹⁰²

Other agents

Other cytokine antagonists are also available for use in steroid‐refractory CRS or patients in which steroid‐sparing is necessary. Clinical and real‐world data for these therapies, however, is more limited. The ASCO guidelines suggest the use of siltuximab, anakinra, or ruloxitinib as the next line in management for those with CRS from CAR T‐cell related toxicity. As stated before, this draws principally on data generated in hematologic cancers and clinician discretion is advised.

Siltuximab is an IL‐6 receptor antagonist ⁶³ , ¹⁰³ that blocks immune effector cell activation via both classical and trans‐signaling pathways. It has a higher affinity for IL‐6 than tocilizumab has for IL‐6R but its clinical data are more limited. There is emerging retrospective trial data to support its efficacy in patients who had CAR T‐cell associated CRS including those who have failed first‐line therapy with tocilizumab. Solid organ tumors were not included in these data. ¹⁰⁴

Anakinra is an IL‐1 receptor antagonist that has shown some success in treating refractory CRS in hematological malignancies. ¹⁰⁵ There are no current data describing its use in solid organ malignancies.

Ruxolitinib, an oral JAK1/2 inhibitor, has been shown to rapidly reduce CRS‐related cytokines, including IL‐6, IL‐10, sCD25, TNF‐γ, and serum ferritin, following administration in a small number of patients with steroid refractory CRS. ¹⁰⁶ Large clinical trial and safety data is lacking with no available evidence in solid organ tumors.

Given the limited evidence for these agents in solid organ tumors, it is essential to reassess the patient’s response, ceiling of care, and suitability before initiating therapy, as the treatment may ultimately prove ineffective.

Immunotherapy rechallenge

Repeated or continuous dosing immunotherapies for solid tumors—most prominently ICIs and BiTEs—create a unique therapeutic dilemma when CRS occurs. Because these agents are often prescribed with palliative rather than curative intent, the clinician must decide whether the potential gain in tumor control justifies the risk of recurrent toxicity after the episode has settled. Data for rechallenging in CRS are limited but there is evidence to suggest that rechallenging with ICIs after other irAEs may not improve overall survival for patients. ¹⁰⁴ Evidence to guide these judgments, although thin, is reassuring at lower CRS grades. In the Karolinska observational cohort of 2672 ICI‐treated patients, 19 individuals were rechallenged after grade 1–2 CRS and three experienced another episode, each again grade ≤2.⁶⁵ A smaller series of ICI‐related CRS likewise documents low recurrence when therapy is resumed after grade 1–2 events. ¹⁰⁵ Data on BiTEs such as tarlatamab are currently limited to case reports. ¹⁰⁶ Although early outcomes appear promising, clinicians should exercise caution due to the absence of robust clinical trial data to date. This may suggest rechallenging after mild CRS in solid organ tumors is relatively safe and should be taken on a case‐by‐case basis with MDT and patient involvement.

When CRS has resolved, three variables can help determine whether retreatment is reasonable. First, the therapeutic goal: tarlatamab in extensive‐stage small cell lung cancer and tebentafusp in first‐line uveal melanoma carry disease‐controlling (if not curative) ambitions, whereas late‐line ICIs are often palliative. Second, on‐treatment efficacy: objective tumor regression or clear symptomatic benefit strengthens the argument for resumption. Third, patient factors—performance status, comorbidities, and personal risk tolerance—must weigh heavily, given that re‐exposure invariably carries risk.

Prevention

To prevent CRS developing into severe grades, administering a lower dose of immune cell therapy to patients with a high tumor burden has proven effective in hematologic malignancies and may also be relevant for solid tumors. ⁶⁹ , ¹⁰⁷ One study employed risk‐adapted CAR T‐cell dosing based on bone marrow blast percentage, resulting in a reduced incidence of severe CRS and neurotoxicity in patients with substantial tumor burdens. This strategy is based on the correlation between CRS severity and tumor burden, where a higher tumor load offers more antigen targets for CAR T‐cells, leading to heightened T‐cell activation, proliferation, and cytokine release. ¹⁰⁸ Preclinical trials indicate that step‐up dosing or subcutaneous administration of bispecific antibodies may reduce the risk of developing CRS, but these approaches do not yet to have enough evidence to become standard practice. ¹⁰⁹ , ¹¹⁰

Ultimately, T‐cell therapies for solid tumors remain largely in clinical trial, with each defining its own CRS prophylaxis and management strategies. Although adherence to trial‐specific protocols is essential at present, the development of unified, evidence‐based management guidelines will be crucial as these therapies move toward broader clinical application.

FUTURE TREATMENTS

Targeting alternative inflammatory pathway components

Itacitinib is a potent, selective JAK1 inhibitor with broad anti‐inflammatory activity for which there is phase 2 randomized control trial data to support its potential future use as a preventative therapy for those receiving immune cell therapy. ¹¹¹ Phase 3 trial data are not yet available, nor are there data to support treatment in solid organ tumors to date. Prophylaxis for patients with hematological malignancies receiving axicabtagene ciloleucel (CAR T‐cell agent) resulted in a lower incidence of CRS and was generally well tolerated.

TNF‐α, produced by activated T‐cells, is a potential primary mediator in triggering a cascade of inflammatory cytokine release from monocytes, leading to the systemic CRS response. Etanercept, a TNF‐α inhibitor, has therefore been suggested as a treatment and has been used with mixed results in hematological malignancies. ¹¹ , ¹¹² Case report data support some success in solid organ malignancy with ICI‐associated CRS after failed use of tocilizumab and steroids but other cases may not respond in a similar way. ¹⁴ Further research is needed to determine its efficacy and safety, as well as its impact on antitumor responses.

Dasatinib is a tyrosine kinase inhibitor that has in vitro evidence for reducing CRS toxicity related to BiTE therapy and case reports in CAR T‐cell treatment. ¹¹³ , ¹¹⁴ Lenzilumab is a monoclonal antibody that neutralizes GM‐CSF, a glycoprotein that promotes macrophage differentiation that in turn leads to the production of IL‐6 and TNF‐α, among others. ¹¹⁴ This has also shown some in vitro success. Clinical trial data are not yet available for these potential future therapies.

Removal of inflammatory mediators

Case reports have demonstrated success for therapeutic plasma exchange (TPE), also known as plasmapheresis, in cases of severe refractory CRS following CAR T‐cell therapy for which tocilizumab and glucocorticoids have failed. ¹¹⁵ , ¹¹⁶ There has also been success in TPE lowering serum levels of IL‐6, CRP, and other inflammatory markers in patients with severe SARS‐Cov‐2–related inflammatory syndrome. ¹¹⁷ The effect of TPE on overall survival is unclear as we do not have sufficient evidence to estimate its effect on the efficacy of immune cell therapy. TPE has been successful in a single case report for a patient with a solid organ tumor, hepatitis B virus‐related metastatic hepatocellular carcinoma with lung metastases, who developed severe refractory CRS after treatment with T‐cell receptor‐engineered T‐cell immunotherapy. ¹¹⁸ We do not yet have supportive evidence from clinical trials.

Suicide genes in immune cell therapy

Suicide gene systems involve engineering T cells with a “suicide” gene that can be activated by administering an external agent to induce apoptosis in the modified T cells. ¹¹⁹ Genes like inducible caspase 9 (iCasp9) or herpes simplex virus thymidine kinase (HSV‐TK) can be triggered by specific drugs to potentially assist with controlling adverse effects. For example, the HSV‐TK gene is one of the most frequently studied suicide genes. It encodes the viral enzyme HSV‐TK, which, in the presence of the drug ganciclovir, converts the drug into its active triphosphate form in pre‐clinical data. This leads to DNA chain termination and cell death in the T cells expressing the suicide gene. ¹²⁰ Although limited to humanized mouse models thus far, administering an agent like AP1903 alongside the iCasp9 construct has shown effectiveness in T and CAR T‐cells for alleviating CRS‐like symptoms and has demonstrated a decrease in proinflammatory cytokine levels. ¹²¹

CONCLUSION

Although the management of CRS in hematological malignancies is well‐researched with established clinical guidelines, CRS in solid organ tumors presents a unique and evolving challenge. Balancing the reduction of inflammation with the preservation of the antitumor immune response is crucial, requiring a patient‐centered approach and personalized care strategies for individual treatment goals. Although supportive care is sufficient for mild CRS, higher‐grade cases often require targeted interventions such as tocilizumab, corticosteroids, or alternative agents for refractory symptoms. Timely involvement of a multidisciplinary team and early escalation to intensive care are often required and should be approached in a proactive manner. The decision to resume immunotherapy, particularly in the context of malignancies being treated with palliative intent, remains a nuanced decision that requires a personalized approach.

Ongoing research is crucial to developing innovative therapeutic strategies. Potential future treatments, such as targeting other components of the cytokine cascade, plasma exchange, and suicide gene systems, show promise in preventing and managing CRS. Continued advancements in this field hold the potential to provide safer and more effective immunotherapy options for patients with solid tumors, paving the way for improved outcomes and enhanced patient care.

AUTHOR CONTRIBUTIONS

David Synnott: Conceptualization, writing–original draft, and writing–review and editing. David O'Reilly: Conceptualization, writing–original draft, and writing–review and editing. Declan de Freitas: Conceptualization, supervision, and writing–review and editing. Jarushka Naidoo: Conceptualization, supervision, and writing–review and editing.

CONFLICT OF INTEREST STATEMENT

David O’Reilly reports consulting fees from Janssen; and conference attendance for Takeda, MSD, and Servier. Jarushka Naidoo reports consulting fees from Bristol‐Myers Squibb, Roche/Genentech, Amgen, NGM Pharmaceuticals, Takeda, Pfizer, Elevation Oncology, AbbVie, Kaleido Biosciences, and Daiichi Sankyo; and grant and/or contract funding from AstraZeneca, Bristol‐Myers Squibb, Roche/Genentech, Amgen, and Mirati. The other authors declare no conflicts of interest.

Synnott D, O’Reilly D, De Freitas D, Naidoo J. Cytokine release syndrome in solid tumors. Cancer. 2025;e70069. doi: 10.1002/cncr.70069

DATA AVAILABILITY STATEMENT

This is a review article. Relevant sources are referenced in article.