Adverse effects of CAR T-cell therapy for non-specialist teams

Chimeric antigen receptor (CAR) T-cell therapy is an advanced form of adoptive cellular immunotherapy in which autologous (i.e. the patient’s own) T lymphocytes are genetically engineered to express synthetic receptors, targeting specific tumour antigens^​1​. These autologous T-cells are modified ex vivo and reinfused to mediate targeted cytotoxicity against malignant cells – a treatment strategy that has demonstrated improved progression-free survival, overall survival and cancer remission rates for multiple haematological malignancies^​1​. Other T-lymphocyte-based therapies have shown potential for improved outcomes in solid tumour malignancy^​1​. Building on this, clinical trials are now exploring their application in non-malignant diseases, notably autoimmune conditions^​2​.

Despite the positive outcomes of CAR T-cell therapy, it comes with the caveat of significant toxicities, such as neurotoxicity, infections and cytokine release syndrome (CRS), which are described in more detail below.

This article aims to equip non-specialist healthcare professionals (HCPs) with practical knowledge on recognising and responding to toxicities following CAR T-cell therapy, with a particular focus on delayed effects, shared-care responsibilities, long-term follow up and escalation pathways. It should be read alongside other advanced therapy medicinal product (ATMP) articles from The Pharmaceutical Journal, see Box 1^​3–5​.

Current and emerging CAR T-cell therapies

The NHS funds several CAR T-cell therapies, all of which target CD19, see Box 2^​6–12​.

Many other CAR-T products are in development, with more than 1,500 active clinical trials registered globally^​1​. Efforts focus on improving efficacy, safety and manufacturing logistics^​1​. 

Why non-specialist teams need awareness of CAR-T products

Non-specialist teams in smaller district general hospitals and primary care settings should be aware of CAR T-cell therapy and its longer-term toxicity risks^​13​. As more patients return to local services after receiving treatment at specialist cell therapy treatment centres, they may present with delayed or chronic complications that require prompt recognition and management outside tertiary settings^​13​.

These complications can include, but are not limited to, prolonged cytopenias (i.e. decreased blood cell counts), late infections and delayed neurotoxicity, which may manifest months to years after infusion and can be mistaken for other conditions if clinicians are unaware of the patient’s CAR T-cell history. Timely recognition and intervention for immune-related adverse events, including CRS, neurotoxicity, hemophagocytic lymphohistiocytosis (i.e. lymphocytes and macrophages attack the body’s own tissues and organs), and infection risk, can reduce morbidity and mortality^​14​.

Recent relaxation of the US Food and Drug Administration’s (FDA’s) risk evaluation and mitigation strategies (REMS) requirements for CAR T-cell therapies, together with updates to CAR-T manufacturer guidance, supporting more flexible outpatient monitoring pathways, reflects a broader international shift toward decentralised follow-up care^​15,16​, as well as underscoring the need for all clinicians involved in longitudinal patient management to be familiar with CAR-T-related toxicity management^​13​.

Acute toxicities of CAR T-cell therapy

CAR T-cell therapy is associated with a range of serious and potentially life-threatening toxicities that require prompt recognition and accurate clinical assessment, as delays or suboptimal management can significantly increase the risk of harm^​13,14​.

In clinical practice, adverse events associated with CAR T-cell therapies are often categorised as acute or delayed, based on their timing relative to infusion, although this temporal framework does not always reflect the underlying pathophysiology, see Figure 1^​14,17​. In addition, lymphodepleting chemotherapy (LDC), most commonly fludarabine and cyclophosphamide administered in the days preceding infusion to optimise CAR T-cell expansion and persistence, contributes its own spectrum of adverse effects, such as neutropenia, thrombocytopenia and increased infection risk, which may overlap with or exacerbate CAR T-cell-related toxicities^{​14,18–20​}.

Figure 1: Approximate timeline of selected CAR T-cell therapy-related adverse events

Acute CAR T-cell-related toxicities typically emerge within the first month following infusion. Their incidence and severity vary by product, underlying disease and individual patient factors. These systemic immune-mediated complications arise from CAR T-cell activation, leading to sustained cytokine release and immune dysregulation^{​13,14,17​}. In addition, on-tumour effects, such as tumour lysis syndrome (TLS), may also occur during this period^​18​. While recognition and management primarily sit with specialist teams, broader awareness among non-specialist HCPs is essential to support continuity of care, particularly when patients present outside designated cell therapy treatment centres — for example, in accident and emergency departments, GP practices or community pharmacies.

Cytokine release syndrome

CRS is the most common early toxicity of CAR T-cell therapy, occurring in 70–90% of recipients^​21​. It reflects a progressive systemic inflammatory response driven by rapid CAR T-cell activation and proliferation, resulting in a large increase in the release of pro-inflammatory cytokines, particularly interleukin-6 (IL-6). This cytokine surge activates bystander immune and non-immune cells, further amplifying inflammation^{​21–23​}. 

CRS typically presents within two to three days of infusion, with severity ranging from mild flu-like symptoms to life-threatening multiorgan failure. Hallmark features – such as fever, hypotension and hypoxia – guide clinical assessment and grading^{​13,21–23​}.

First-line treatment for moderate-to-severe CRS is the IL-6 receptor antagonist, tocilizumab, which is nationally commissioned for this indication, with funding approved for up to four doses per patient^​18​. Corticosteroids and other anti-cytokine therapies (e.g. anakinra, siltuximab) are reserved for cases refractory to tocilizumab or for higher-grade CRS, although clinical trial data is lacking^{​13,18,21​}. Supportive care, including antipyretics, broad-spectrum antibiotics and intravenous fluids is essential^​18,21​. Around one-quarter of patients require intensive care for severe CRS, including vasopressor support and mechanical ventilation^​24​. 

Immune effector cell-associated neurotoxicity syndrome

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a distinct complication of CAR T-cell therapy, occurring in 20–40% of recipients^​25​. Its multifactorial pathophysiology involves blood-brain barrier disruption, cytokine-driven endothelial activation and immune cell trafficking into the central nervous system (CNS), resulting in neuroinflammation, coagulopathy and neuronal dysfunction^{​13,23,25​}.

ICANS typically presents within four to ten days of infusion, often overlapping with or following CRS. Clinical features range from encephalopathy, aphasia and cognitive impairment to motor weakness, seizures, and, in rare cases, cerebral oedema and death^{​13,23,25​}.

Although most cases occur acutely, a minority of patients develop delayed-onset ICANS, which emerges after the resolution of CRS and within the first month of CAR-T infusion. Symptoms mirror those of acute ICANS and may fluctuate or recur after apparent improvement or persist as subacute cognitive dysfunction^​26,27​. Episodes are usually self-limiting, with symptoms lasting 5–17 days^​26​. 

ICANS is a major cause of morbidity in CAR T-cell therapy and requires prompt recognition and intervention. Management relies on corticosteroids titrated to severity, alongside supportive care including levetiracetam for seizure prophylaxis^{​13,18,23,25​}. Between 17–35% of recipients require intensive care support. 

With timely intervention, ICANS is reversible, although severe cases may lead to prolonged deficits, or rarely, fatal outcomes. Long-term follow-up is therefore warranted^​25​. In addition, manufacturers advise that all patients undergoing CAR T-cell therapy should refrain from driving or operating heavy machinery for at least eight weeks post-infusion, regardless of whether neurotoxicity occurs^​16​.

Immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome 

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a rare but potentially fatal hyperinflammatory toxicity associated with CAR T-cell therapy, occurring in up to 3.5% of recipients^​13​. It is driven by excessive activation of T-cells and macrophages, leading to a cytokine storm and multiorgan dysfunction^​21,28​.

Diagnosis is challenging, as IEC-HS overlaps clinically and temporally with CRS and ICANS^​13,28​. Clinical and laboratory features resemble classical hemophagocytic lymphohistiocytosis (HLH), including persistent fever, cytopenia, hyperferritinaemia, hypofibrinogenaemia, transaminitis, coagulopathy and evidence of hemophagocytosis^{​13,21,28​}.

Prompt recognition and treatment are essential, as IEC-HS can progress to multiorgan failure and death^{​13,21,28​}. First-line therapy consists of corticosteroids, with cytokine-targeted agents, such as anakinra (IL-1 blockade) and ruxolitinib (JAK inhibition), considered in refractory cases^{​13,21,28​}.

Sepsis

Sepsis is a determinant of hospitalisation and non-relapse mortality in CAR T-cell recipients^​29,30​. It most commonly occurs within the first month following therapy, with the highest risk during the initial 10–14 days post-infusion, coinciding with neutropenia and acute immune effector cell (IEC)-associated toxicities^{​1,22,29​}. Reported incidence ranges from 5–32%, with bacterial infection predominating^​1,29​. Although sepsis represents the principal early infectious presentation, other early infections, including herpesvirus reactivation may also occur^​31​.

Clinical presentation may be indistinguishable from CRS and other IEC-associated toxicities, making diagnosis challenging. Careful clinical assessment, microbiological evaluation and prompt initiation of empirical broad-spectrum antibiotics are essential to reduce morbidity and mortality^{​18,21,31​}.

Delayed effects of CAR T-cell therapy

The principal late complications of CAR-T therapy are outlined below. Compared with early toxicities, late effects are less well characterised and inconsistently reported^​32,33​. 

Prolonged neurologic symptoms following ICANS

While ICANS is typically self-limited, around 27% of patients who develop ICANS experience prolonged neurologic deficits that persist beyond four weeks^​26​. Clinical manifestations include impairments in short-term and long-term memory, aphasia and tremor^​26,27​. 

Risk factors for prolonged neurological symptoms are not fully established, although high-grade (grade ≥3) acute neurotoxicity has been consistently associated with incidence, affecting 42% of this subgroup, compared with only 7% of those with low-grade ICANS^​26​. 

Management of prolonged symptoms follows standard ICANS treatment algorithms, with supportive care and ongoing monitoring recommended^​26,27​.

Non-ICANS neurological complications

Although no BCMA-directed CAR T-cell therapies are available within the NHS, it is important to note that they are associated with distinct non-ICANS delayed neurological complications, including IEC-Parkinsonism and cranial nerve palsies. These complications are considered a class effect of BCMA-targeting, with the mechanism thought to involve on-target CAR T-cell activity within the CNS, although this is not yet fully established^​34​.

Immune effector cell-associated haematotoxicity and infection risk

Cytopenias, particularly neutropenia, are the most common high-grade adverse events following CAR T-cell therapy. Although the underlying pathophysiology remains unclear, the pattern suggests a class-wide effect, characterised by profound and persistent cytopenia that may last for months to years after infusion, often with periods of intermittent count recovery^​31,35​. Prolonged grade 3–4 cytopenias occur in 30–40% of patients beyond Day +30 and there are varied reports in 3–22% of patients beyond Day +90 after CAR-T infusion^​36​. This clinical phenotype is recognised as immune effector cell-associated haematotoxicity (ICAHT), a distinct entity with its own consensus-driven grading system and a corresponding severity-based management algorithm^{​31,35,37​}.

The risk of immunosuppression following CAR T-cell therapy is multifactorial and can predispose patients to severe infectious complications and inferior survival, with infections being the leading cause of non-relapse mortality^​31,35​. Although the most severe infections occur within the first 28 days, late infections, particularly upper respiratory viral infections, are frequently observed months to years after CAR-T therapy. While ongoing care is typically coordinated between the cell therapy treatment centre and referring haematology teams, patients may present acutely to local services, making awareness of their prolonged immunocompromised status essential for non-specialist clinicians. Late infections can result in repeated hospitalisation, increased healthcare contact and poorer quality of life. Although uncommon, life-threatening invasive fungal infections have also been reported³². The use of granulocyte-colony stimulating factor (G-CSF) and anti-infective prophylaxis is therefore recommended, with duration typically guided by the extent of immune reconstitution. Management of suspected or confirmed infections should follow institutional guidelines^​18,31​, see Box 3^​26,31​.

B-cell aplasia and hypogammaglobulinaemia are recognised ‘on-target/off-tumour’ complications of CAR T-cell therapy directed against B-lineage antigens, occurring in 44–53% of patients — increasing susceptibility to infection and necessitating coordinated long-term follow-up between treating and referral centres^​31,36​. Recovery patterns are variable but often prolonged, frequently extending beyond six months and requiring immunoglobulin replacement therapy (IGRT)^{​18,31,37​}, which is nationally commissioned for patients with secondary immunodeficiency following CAR-T therapy^​38​. Vaccination forms a vital part of long-term immune reconstitution, as discussed below.

Primary disease relapse and secondary malignancies

Primary disease relapse remains the most common cause of treatment failure after CAR-T therapy, occurring in about 40–60% of patients within 1–2 years, with rates varying by disease, CAR construct and patient-specific factors. Relapse may arise from antigen loss, inadequate CAR-T expansion or persistence, or aggressive underlying disease biology. Patients who relapse often require further immunosuppressive therapy, contributing to cumulative marrow toxicity and an increased risk of infection^​1,36​. Ongoing surveillance is therefore essential to detect relapse early and guide subsequent management^​39​.

Secondary malignancies have a cumulative incidence of up to 6.5% at 3 years^​40​. Most are myeloid neoplasms, with smaller proportions of solid tumours; secondary T-cell malignancies are rare, occurring in about 0.1% of patients^​41,42​. Risk appears related to older age, multiple prior cytotoxic therapies, clonal haematopoiesis and longer follow-up, and does not appear higher than in comparable populations receiving other standard therapies. Cases are typically detected through routine surveillance^{​27,41,42​}. Although isolated reports of CAR transgene-positive T-cell cancers have been described, causality remains unproven. Nonetheless, regulatory agencies have advised lifelong monitoring^{​42–44​}.

Supportive care and patient empowerment

Supportive care measures, including individualised risk assessment, infection prophylaxis and immunoglobulin replacement are essential for mitigating long-term risks^​45​. 

Vaccination guidance

UK vaccination guidelines recommend that all routine immunisations be repeated after CAR T-cell therapy, regardless of prior vaccination status^​46​. Influenza and COVID-19 vaccines may be administered from three months post-infusion, while other non-live (inactivated) vaccines should generally be deferred until at least six months after therapy for optimal immunogenicity^​46​. Guidance suggests an optimal window of 6–18 months owing to prolonged B-cell aplasia and hypogammaglobulinemia, which can impair vaccine responses^​46​.

Patients with persistent hypogammaglobulinemia or ongoing B-cell–depleting therapies may mount reduced responses, but vaccination remains recommended to lower the risk of severe infection^​46​.

Live and live-attenuated vaccines are contraindicated for at least two years following CAR-T therapy and should only be considered if there is no ongoing immunosuppression or B-cell dysfunction^​46​.

These recommendations reflect the high risk of infection and loss of pre-existing immunity after CAR-T therapy and the need to optimise protection despite potentially reduced vaccine efficacy^​46​.

Red-flag symptoms and skilled-task restriction counselling

Severe toxicities, particularly within the first eight weeks post-infusion, require vigilant monitoring and clear patient education about early and late effects. Red-flag symptoms requiring urgent medical attention during this period are summarised below, see Box 4^​14​.

Skilled-task restrictions, such as driving or operating heavy machinery, require careful consideration in all CAR T-cell therapy recipients. In the UK, manufacturer summary of product characteristics (SmPC) advise that patients avoid skilled tasks for at least eight weeks post-infusion, regardless of whether neurotoxicity occurs, or until any neurologic adverse events have fully resolved^​18​. In practice, consensus guidance emphasises that restrictions should be individualised, particularly in the presence of neurotoxicity or other adverse effects that may impair a patient’s senility to safely perform skilled tasks^​13​.

Patient and caregiver education should include written instructions and emergency contact information, emphasising the importance of promptly reporting symptoms to the cell therapy treatment centre or specialist team rather than attempting to self-manage red-flag concerns^​13​. The optimal duration and criteria for lifting skilled-task restrictions remain under investigation, as late-onset neurotoxicity and other adverse effects may occur beyond the initial monitoring window^​13​.

The use of alert cards or medical bracelets, carried at all times after receiving CAR‑T therapy, helps ensure rapid recognition of a patient’s treatment history by HCPs and supports timely escalation during acute illness. These tools also empower patients to notify HCPs early if symptoms or concerns arise^​13​.

Shared care

Survivorship care plans (SCPs) are recommended to support communication and individualised follow-up between cell therapy treatment centres, referring teams and primary care. SCPs should outline the CAR-T product administered, anticipated toxicities, recommended surveillance intervals and clear triggers for referral^​13​. Patients are followed for up to 15 years as part of post-authorisation safety surveillance (PASS) requirements, including registry participation, to monitor long-term safety and outcomes^​13,44​.

Non-specialist teams play a critical role in long-term monitoring, early recognition of late toxicities and coordination of care. A multidisciplinary approach is essential, with regular updates from the cell therapy treatment centre, defined referral pathways for acute or late complications, as well as shared protocols for surveillance and supportive care^{​13,27,44​}. Non-specialist clinicians should be prepared to promptly refer patients with hematologic, infectious or neurological complications, and to collaborate closely with specialist teams in the management of complex, late effects^​13,27​.

Referral triggers and escalation pathways

Late complications resulting from CAR-T therapy should be escalated to the patient’s cell therapy treatment centre. In the UK, patients are monitored intensively during the initial post-infusion period, with clear pathways for managing acute toxicities^{​27,33,44​}. After discharge, patients remain within proximity to the cell therapy treatment centre until at least Day +30 and are advised to return immediately if they develop fever, neurological symptoms or other signs of toxicity^​47​. 

Long-term follow-up is delivered through shared-care arrangements between commissioned cell therapy treatment centres and local haematology teams, enabling regular, systematic and longitudinal surveillance^{​27,33,44​}. Late complications may present with subtle or non-specific symptoms, so a low threshold for seeking specialist advice is advised^​13,33​. All patients should carry a product-specific CAR-T alert card to support rapid recognition and escalation^​27​. Supportive care, including anti-infective prophylaxis, IGRT and vaccination schedules, should be communicated and managed jointly. Local teams should ensure they have access to the cell therapy treatment centre’s 24-hour contact details for urgent advice^​27,47​.

Clear referral triggers and standard escalation pathways between the cell therapy treatment centre, the referring haematology team and non-specialist services are essential to ensure timely communication and multidisciplinary assessment whenever late complications are suspected^{​27,33,41​}. Most cell therapy treatment centres run dedicated late-effects clinics and use SCPs to outline monitoring schedules and coordination between HCPs^​27,33​. Adverse effects should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) via the Yellow Card Scheme, and ongoing surveillance contributes to national and international registries, see Box 5^{​27,33,41,44​}.