Significant strides have been made in recent years in the management of cancers across the patient lifespan. According to the US Medicines in Development for Cancer 2020Report, more than 1300 medicines and vaccines targeting a wide variety of cancers are currently being developed, in ongoing clinical trials, or awaiting review by the US Food and Drug Administration (FDA) (Pharmaceutical Research and Manufacturers of America, 2020). As of 2021, the UK's Institute of Cancer Research reported that there were a total of 228 905 individuals who were enrolled and recruited into clinical trials for the treatment of all types of cancer in the years 2017 to 2021 (Institute of Cancer Research, 2021).
Advances in scientific knowledge, bolstered by a better understanding of the biology, natural history and genetics of cancer cells, have led to the discovery of novel pathophysiologic pathways involved in the malignant transformation of an otherwise healthy human cell. The wide explosion of new information elucidating the molecular mechanisms involved in disease pathogenesis have helped in the development of potential therapeutic options, which are not only targeted to the disease pathways but, more importantly, are safer, well tolerated and accessible to individual patients. This narrative review describes the physiology of chimeric antigen receptor (CAR) T-cell therapy, its advantages, and its risks and complications, and is accompanied by an illustrative case study (Box 1). The future prospects of CAR T-cell therapy are explored, as well as its implications for nurses and other healthcare providers.
Case study
David Smith (not his real name), aged 23, was diagnosed with diffuse large B-cell lymphoma 3 years ago after presenting to his GP with unexplained fever, weight loss and night sweats. He initially underwent six cycles of first-line R-CHOP immuno-chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) but relapsed 6 months after completing treatment.
He was considered for high-dose chemotherapy with autologous stem-cell transplantation (HDCT-ASCT) but was deemed ineligible due to unsuccessful stem cell collection. Instead, he received second-line immuno-chemotherapy of R2-ICE (rituximab, ifosfamide, carboplatin, etoposide) plus oral lenalidomide but relapsed after completing four cycles. An interval PET-CT scan revealed persistent abdominal lymphadenopathies, and new enhancing lesions in the chest and neck.
Following a multidisciplinary team discussion, David was identified as a potential candidate for CAR T-cell therapy and was promptly informed of the treatment plan.
Stage 1: eligibility, patient selection and consent
The nurse's primary role at this stage was to provide David and his family with clear, factual information about the CAR T-cell therapy process. The CAR T-cell therapy pre-treatment phase includes assessing treatment eligibility, conducting a thorough evaluation of disease status (such as further imaging, blood tests and tissue biopsy), and performing a comprehensive functional assessment.
David was at an advanced stage of disease, therefore a realistic discussion about his prognosis was essential. David was electively admitted to the oncology ward after the successful collection and processing of T-cell products. He underwent a lymphodepleting preconditioning chemotherapy of cyclophosphamide and fludarabine. He then received an infusion of axicabtagene ciloleucel at a dose of 2.5 × 106 CAR T-cells/kg, without any immediate adverse effects. His vital signs remained stable for the first 2 days post infusion.
Stage 2: lymphodepletion and CAR T-cell infusion
Due to the complexity of the CAR T-cell therapy process, multidisciplinary team involvement in David's care was essential. At this stage, the nurse's primary role was to ensure the safe administration of chemotherapeutic agents and CAR T-cell products. Nurses educated David and his family about the purpose of lymphodepletion, the effects of the therapy itself, and the potential risks, complications, and early symptoms that should be promptly reported to healthcare providers.
David's vital signs were monitored before, during and after the infusion. Strict adherence to infection prevention and control measures was crucial, as David was functionally immunosuppressed and highly vulnerable to infections.
On Day 3 of treatment, David developed a fever of 38.2°C unresponsive to intravenous paracetamol, along with a new-onset cough, shortness of breath and oxygen desaturation of 86%, which improved with 4 litres of supplemental oxygen via nasal cannula. Later in the day, his blood pressure dropped to 70/35 mmHg and remained low despite a 2-litre bolus of Hartmann's solution. His oxygen saturations continued to decline to 86% despite receiving 40% oxygen via a Venturi mask.
Despite these developments, David remained fully alert, orientated, and without any neurological deficits. He was transferred to the intensive care unit and started on a noradrenaline infusion which helped maintain a mean arterial pressure of 70 mmHg. He was started on high-flow oxygen therapy with 60% FiO2 at a flow rate of 60 L/min. A chest CT showed no obvious infiltrates, and he was initiated on empirical broad-spectrum antimicrobial therapy with meropenem, vancomycin and micafungin. Given his ASTCT CRS grade 3 classification (see Table 1), he also received intravenous tocilizumab. David remained in the ICU for 5 days before being discharged back to the oncology ward without the need for vasopressor or respiratory support.
| CRS parameter | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|
| Fever* | Temperature ≥38°C | Temperature ≥38°C | Temperature ≥38°C | Temperature ≥38°C |
| 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 oxygen delivery | Requiring high-flow nasal cannula‡, face mask, non-rebreather mask, or Venturi mask | Requiring positive pressure (eg CPAP, BiPAP, intubation and mechanical ventilation) |
Stage 3: post-infusion observations and monitoring of complications
Complications related to CAR T-cell infusion are common and often present a few days after the initial treatment. Understanding and recognition of the early signs of complications are crucial, as these conditions can present with subtle or subacute symptoms and can be easily missed. Neurological monitoring continued to detect any early signs of immune effector cell-associated neurotoxicity syndrome (ICANS). A multidisciplinary team approach remained crucial, with input from physiotherapists, nutritionists and dietitians, among others, to prevent deconditioning and to support David's rehabilitation and early discharge planning.
Cancer statistics in the UK
In 2015, a nationwide population study in the UK showed that there had been a substantial increase in cancer survivorship over the preceding 40 years. Five-year net survival rates improved from 25% in 1971-1972 to 49% for men in 2010-2011, and from 34% to 59% for women over the same period (Cancer Research UK, 2014; Quaresma et al, 2015). Despite these significant advances in cancer outcomes, malignant neoplasms continue to be one of the leading causes of death across all age groups in the UK. Cancer is the cause of just over one quarter of all deaths in England in a typical year (Harker, 2024). Projections using age-period-cohort models suggest that, within the UK, the average number of deaths from all cancers combined will rise from 176 000 in 2023-2025 to more than 208 000 by 2038-2040 (Cancer Research UK, 2022).
In 2019, NHS England introduced the NHS Long Term Plan (NHS England, 2019), which outlined an ambitious commitment to improving cancer services and outcomes across the UK over the next decade. The key goals of the plan include increasing the proportion of people diagnosed with cancer at an early stage (stage 1 or 2) and improving the 5-year survival rate for those living with the disease. The Long Term Plan was designed to enhance the quality of life and patient experience of individuals with cancer, at the same time as addressing and reducing disparities and inequalities in cancer care delivery. To achieve these objectives, the NHS has emphasised the importance of providing access to high-quality, personalised care interventions that are tailored to individual needs and are focused on long-term health and wellbeing. As part of this plan, the introduction of innovative treatments, such as CAR T-cell therapy, have been integrated into the NHS's repertoire of services.
Discovery and introduction of CAR T-cell therapy in clinical practice
In 1993, the first CAR T-cells were developed by constructing and combining chimeric genes containing variable regions of an antibody and integrating them into T-lymphocytes, thereby conferring antibody-like specificity (Eshhar et al, 1993). However, these first-generation CAR T-cells were largely unsuccessful in clinical trials primarily due to their low persistence, limited anti-cancer activity, and inadequate proliferation in vivo (Mitra et al, 2023). Over the past decade, refinement, sophistication and modernisation of CAR T-cell manufacturing techniques have led to the development of CAR T-cell with enhanced anti-tumour activity, cytokine secretion and T-cell proliferation, as well as improved in vivo persistence and resistance to apoptosis (Styczyński, 2020).
In 2002, researchers at Memorial Sloan Kettering Cancer Center in New York developed the first human CAR T-cells that successfully targeted prostate-specific cancer antigens, killing prostate cancer cells in vitro (Maher et al, 2002). Eight years later, clinical effectiveness of second-generation CAR T-cells was demonstrated when a patient at the National Cancer Institute in Maryland achieved partial remission of advanced follicular lymphoma during CAR T-cell treatment (Kochenderfer et al, 2010). On August 30, 2017, the US FDA approved the first CAR T-cell therapy, tisagenlecleucel (Kymriah®, Novartis Pharmaceuticals), for the treatment of paediatric and young adult acute lymphoblastic leukaemia (ALL) (Maude et al, 2018). Subsequently, on 28 June 2018, the European Medicines Agency (EMA) approved its use in children and young adults aged up to 25 years with B-cell ALL who do not respond to treatment or have relapsed two or more times (EMA, 2022a).
In September 2018, the NHS and the National Institute for Health and Care Excellence (NICE) approved the administration of the first CAR T-cell therapy in the UK, tisagenlecleucel, for the treatment of refractory or relapsed B-cell ALL in children and adults up to the age of 25 (NICE, 2018). Later that year, in December, the second CAR T-cell therapy, axicabtagene-ciloleucel (Yescarta®, Kite Pharma/Gilead), was approved for the treatment of adult patients with relapsed large B-cell lymphoma through the NHS Cancer Drugs Fund (NICE, 2023a).
In a landmark 2018 decision, NHS England authorised the implementation of CAR T-cell therapy in designated NHS trusts and centres across the UK, with an option of expanding to additional centres nationwide. This initiative was supported through collaborations between NHS England, the Joint Accreditation Committee ISCT-Europe (JACIE), the European Society for Blood and Marrow Transplantation (EBMT), and various pharmaceutical and life science companies, which facilitated the provision of these therapies at a reduced cost. As of 2019, 25 countries use CAR T-cell technologies as a treatment option for cancer (NICE, 2019; Barros, 2022). In January 2023, NICE announced that axicabtagene-ciloleucel would be routinely commissioned and available within the NHS for the treatment of eligible patients with specific types of lymphoma, and in, June 2023, the third CAR T-cell agent, brexucabtagene autoleucel (Tecartus ®, Kite Pharma/Gilead), received approval for use in select patients with B-cell ALL.
Mechanism of action and principles: review of relevant physiology
T lymphocytes are a subset of white blood cells that originate from the common lymphoid progenitor in the bone marrow before migrating to the thymus (thymic stroma), where they mature and differentiate (becoming thymus-dependent, or T, cells). Immature T-cell progenitors initially lack T-cell receptors (ie, CD4 or CD8) on their membranes until they undergo selection events in the thymic medulla involving an organised expression of various cluster of differentiation (CD) surface molecules and V, D, and J gene rearrangements (Burt and Verda, 2004). This process results in the release of a single positive (CD4+ or CD8+ SP) T-cell repertoire from the thymic cells, which then emigrates and continuously recirculates throughout the bloodstream, peripheral tissues and other lymphoid tissues (lymph nodes, Peyer's patches, spleen) where they become primed and activated to perform different specialised functions (Redelinghuys and Crocker, 2010).
T-cells are a crucial component of the adaptive immune system, with primary functions that include:
T-cells are traditionally classified based on their functional roles (helper CD4+, cytotoxic CD8+, memory, regulatory CD4+, innate-like, natural killer, etc), which is dependent on their cell surface structure and role in immune defence, although several subsets and subpopulations exist, each performing a range and variety of physiologic activities (Janeway et al, 2001). Collectively, however, T lymphocytes facilitate a central role in the orchestration of all functions of the adaptive immune system. In particular, CD4+ T-cells demonstrate helper activities, effector functions and other regulatory activities, including the activation of other T-cells (cytotoxic T-cells), and the release of cytokines to orchestrate a variety of immune functions. CD8+ T-cells play an important role in the control and eradication of intracellular pathogens, the suppression of viral replication, and the detection and destruction of cancer cells through their cytotoxic activity and release of interferon-γ and tumour necrosis factor-α (Mittrücker et al, 2014).
What is CAR T-cell therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a personalised form of immunotherapy in which a patient's own T-cells are genetically modified to express specific receptors that target tumour-associated antigens. These engineered T-cells are subsequently administered to target and destroy cancer cells displaying the corresponding antigens. CAR T-cell therapy has been shown to be very effective against certain types of relapsed and treatment-refractory haematologic malignancies. Notable clinical successes have been observed in the treatment of B-cell and acute myeloid leukaemia (Shahzad et al, 2023), B-cell lymphoma (Shargian et al, 2022), and multiple myeloma (Zhang et al, 2021). At present, all CAR T-cell therapies approved by the US FDA, EMA in the EU and NICE in the UK are indicated for the treatment of haematologic malignancies in both adult and paediatric populations.
Compared to normal cells, tumour and cancer cells express tumour-associated antigens that are genetically different from those found on their healthy counterparts (Jayaraman et al, 2020). Engineered CARs can identify and discriminate these tumour-associated antigens with great specificity, and the ability of CAR T-cells to effectively recognise these tumour-associated antigens is crucial in predicting CAR T-cell response and treatment success (Hanssens et al, 2022). In most FDA-approved CAR T-cell products, the antigen-binding domain is comprised of a single-chain variable fragment (scFv) molecule derived from a monoclonal antibody (such as mouse anti-human CD19 antibodies), although other molecules (such as nanobodies, cytokines, peptides, and other ligands) have been used more recently in newer generation CARs (Rafiq et al, 2020).
When an antigen binds to the antigen-recognition domain on the surface of a CAR T-cell, the CARs aggregate, leading to the transmission of an activation signal. This signal initiates intracellular signal transduction pathways that are crucial for both T-cell activation and co-stimulation (Ahmad et al, 2022). The T-cell activation domain consist of CD3ζ-derived immunoreceptor tyrosine-based activation motifs, which, when phosphorylated, catalyses the activation of signalling pathways involved in the generation and production of effector T-cell responses (Honikel and Olejniczak, 2022). Activated T-cells elicit anti-tumoural activity through a variety of mechanisms that include perforin and granzyme-targeted cell lysis, inflammatory cytokine secretion, and activation of Fas and Fas Ligand pathways.
After engagement with the target cell, secretory granules containing a variety of cytotoxic molecules migrate to the immunological synapse and fuse with the target cell plasma membrane. Perforin, a cytolytic protein, is released from the granules and forms channels or pores into the target cells where granzymes, a group of powerful serine proteases, are released, leading to the activation of intrinsic and caspase-mediated apoptotic pathways leading to cell death (Pardo et al, 2009). T-cell activation also leads to the release of a wide range of inflammatory cytokines, which play a major role in orchestrating a variety of immunological functions, including inducing inflammation, promoting immunogenic cell death and altering the tumour micro-environment to modulate anti-tumoural responses. This plays an important role in the development of CAR T-cell-related complications (Ahmad et al, 2022).
Finally, ligand-binding and activation of the Fas pathway results in the activation of the death receptor family of apoptosis-inducing cellular receptors, which induces tumour cell lysis and subsequent cell death (Benmebarek et al, 2019).
Clinical development and manufacture of CAR T-cell therapies: step 1 for the patient
The CAR T-cell therapy process begins with the collection, selection and isolation of T lymphocytes from the patient's blood. This is achieved through leukapheresis, a procedure in which whole blood is extracted from the patient using commercially available automated continuous-flow apheresis machines. These machines separate blood components, and isolate and collect lymphocytes in quantities sufficient for subsequent manufacturing and treatment (Korell et al, 2020). The primary goal of leukapheresis is to optimise the efficiency of lymphocyte collection and enhance yield, thus ensuring that the resulting leukapheresis product meets the necessary volume, quality and viability requirements for effective CAR T-cell production (Qayed et al, 2022).
After collection, T-cells undergo a thorough washing process to eliminate contaminants, followed by an enrichment phase that yields a homogeneous population of CD4+ and CD8+ T-cells. This enrichment is crucial because it enhances transduction efficiency and optimises T-cell activation during the subsequent CAR T-cell processing (Noaks et al, 2021). The cell cultures are then subjected to monocyte depletion, a step that has been shown to improve tumour-killing efficacy, T-cell stemness (the ability to self-renew), in vivo expansion, and CAR T-cell persistence (Wang et al, 2021). Naïve, resting T-cells are then activated, that is, stimulated to undergo a robust expansion and proliferation, through stimulation with autologous antigen-presenting cells, superparamagnetic beads coated with monoclonal antibodies, and various growth factors or interleukins, to induce rapid T-cell growth (Zhang et al, 2017).
The subsequent phase involves the delivery of genetic material into the T-cells using both viral- and non-viral methods (Levine et al, 2017). Current FDA-approved CAR T-cell therapies rely on the use of disarmed retroviruses or lentiviruses to introduce the packaged genetic material into activated T-cells. The transgene, encoding a synthetic antigen receptor, is integrated into the T-cell genome via plasmid-based transposon/transposase systems, viral vectors and, more recently, clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 DNA endonuclease enzyme (Dimitri et al, 2022). Once integrated into the T-cell genome, the DNA is transcribed and translated into the CAR protein, which is then transported, expressed and incorporated in the T-cell's plasma membrane.
The CAR population is expanded in bioreactor culture systems enriched with conditions that facilitate the growth of a large number of cells. Once the cell expansion process is completed, the cell culture is collected, washed and concentrated to an acceptable amount or volume before being transfused to individual patients (Levine et al, 2017).
Role of lymphodepletion in CAR T-cell therapy: step 2 for the patient
Patients who are to receive CAR T-cell therapy undergo a preconditioning regimen that involves the administration of lymphodepleting chemotherapy. This is designed to reduce both the tumour burden and the number of normal immune cells. Reducing tumour burden below the equilibrium threshold enhances the sensitivity of malignant cells to CAR T-cell activity, as larger tumours are more likely to contain greater amounts of immunosuppressive cells that can dampen the antitumour activity of the adoptive cells (Kim et al, 2021). Induction of lymphodepletion, that is, reducing and modulating the patient's own lymphocytes, is critical because it promotes an immune environment that is conducive to effector expansion and persistence (Amini et al, 2022). This process establishes a more favourable niche for the CAR T-cell engraftment, mitigates the rapid exhaustion of CAR T-cell products, and ensures optimal homing, survival and long-term activity of the implanted effector cells (Lickefett et al, 2023).
From a clinical perspective, the combination, type, dosing, intensity and timing of the lymphodepleting regimen are crucial in CAR T-cell therapy, as these factors collectively and synergistically enhance the efficacy of anti-tumour activity beyond what each component could achieve individually (Wang et al, 2023a). An effective lymphodepletion strategy can reduce the required dose of CAR T-cells necessary to achieve a successful effector response, thereby minimising the risk of severe, life-threatening toxicities (Lickefett et al, 2023). Additionally, modelling studies also suggest that the duration between the completion of preconditioning chemotherapy and the CAR T-cell infusion, known as the recovery period, is also critical (Owens and Bozic, 2021). Timing the CAR-T therapy to coincide with the peak of tumour-cell lysis can optimise T-cell efficiency in targeting and eliminating cancer cells.
CAR T-cell therapy: complications and management: step 3 for the patient
The administration of CAR T-cells is associated with substantial risks, including a wide range of immune-related adverse events, and nurses in oncology and critical care settings play an important role in the management and care of patients receiving CAR T-cell products (Cappell and Kochenderfer, 2023). CAR T-cell therapy can lead to various complications, and early recognition of life-threatening signs and symptoms, alongside timely referral and involvement of the critical care team, is essential to prevent irreversible clinical sequelae and devastating complications.
Cytokine release syndrome
Cytokine release syndrome (CRS) is the most prominent and commonly reported acute toxicity of CAR T-cell therapy, and is reported to occur in up to 97% of patients receiving CAR T-cell products (Messmer et al, 2021). CRS is a form of systemic inflammatory response (Shimabukuro-Vornhagen et al, 2018) that occurs as a result of the release of supraphysiologic amounts of inflammatory cytokines, including interleukin-6 (IL-6), interferon gamma (IFN-γ), interleukin-10, and interleukin-2, into the bloodstream (Lee et al, 2014).
Following CAR T-cell infusion, the T-cells ‘traffic and migrate’ by moving to the tumour site where they recognise and bind to the target cells via their antigen-specific expression site. This binding triggers CAR T-cell activation, leading to massive proliferation, expansion and accelerated in situ cytokine production, thereby enhancing the tumour-killing response (Gauthier et al, 2018). Additionally, immune cells (that is, macrophages and monocytes) within the tumour microenvironment, as well as other circulating or ‘bystander’ immune cells, become activated, further amplifying the immune response and releasing additional cytokines (Siegler and Kenderian, 2020). The resulting systemic inflammatory response can result in endothelial injury and increased vascular permeability across different tissues, potentially leading to hypoxia, hypotension and other associated end-organ dysfunction (Morris et al, 2022).
CRS usually manifests with constitutional symptoms (malaise, fatigue, myalgia, nausea) with fever being one of its hallmark symptoms, and is one that is required for diagnosis and grading of severity (Messmer et al, 2021). The intensity of CRS symptomatology can range from being mild and self-limiting, to severe and life-threatening, which includes some degree of cardiovascular, respiratory, neurological, renal, gastrointestinal and haematologic involvement (Dholaria et al, 2019). The typical onset of CRS occurs between the first and seventh day of the CAR T-cell treatment, which coincides with the peak of the CAR T-cell population expansion, but it can also manifest for up to a couple of weeks after therapy (Siegler and Kenderian, 2020). The intensity and magnitude of CRS also appears greater with patients who have a bigger tumour burden because this leads to higher magnitude of T-cell activation (Lee et al, 2014). It has also been suggested that higher pre-transfusion levels of circulating monocytes lead to greater CRS severity, suggesting that depleting monocyte levels prior to CAR T-cell treatment can lead to lesser CRS intensity (Norelli et al, 2018).
Early diagnosis and timely evaluation of CRS are critical for effective management. Advances in understanding CRS pathophysiology, coupled with the necessity to standardise various grading scales, led to the development of the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system for CRS (Table 1). This grading system, which is now widely adopted, categorises CRS severity based on the presence of fever and the degree of hypotension and/or hypoxia, ranging from grade 1 to grade 4, with grade 4 indicating the most severe and life-threatening conditions, often associated with a poorer prognosis (Lee et al, 2019).
Given that most CRS symptoms are constitutional in nature, supportive care measures are essential and should be consistently implemented across all stages of CRS management (Lee et al, 2014). Febrile episodes should be addressed with antipyretics (such as paracetamol or NSAIDs) or other cooling measures (fans, blankets), as tailored and appropriate to the individual patient's needs. Given these patients’ various degrees of immunosuppression, the aetiology of fever should be comprehensively investigated (Cajanding, 2023). The presence of potential infection should be thoroughly evaluated through microbiologic cultures and imaging, and broad-spectrum antimicrobials promptly initiated if clinically warranted.
Patients with CRS frequently develop hypotension, necessitating aggressive fluid resuscitation and, in more severe cases, vasopressors to establish haemodynamic stability. Hypoxia, desaturation or respiratory distress may also be common, and may require oxygen supplementation delivered via non-invasive respiratory adjuncts (low-flow nasal cannula, high-flow oxygen, Venturi mask), positive pressure ventilation (CPAP, BiPAP) or through intubation and mechanical ventilation. Patients experiencing significant respiratory or cardiovascular compromise will require intensive care admission to manage end-organ dysfunction and prevent further deterioration.
More recently, reports have suggested that prophylactic or early administration of corticosteroids can decrease CRS severity, or shorten its duration (Lakomy et al, 2023). Corticosteroids, such as dexamethasone, work by inhibiting the hyperactivation of macrophages and preventing the liberation of inflammatory cytokines, which causes the CRS symptoms. In cases of severe or life-threatening CRS, the administration of the IL-6 receptor antagonist, tocilizumab, has shown significant clinical efficacy. Tocilizumab not only reduces the severity of CRS but also decreases the incidence of organ toxicities and, when used prophylactically, lowers the overall occurrence of CRS (van de Donk et al, 2023).
Additionally, other agents that have been investigated for the management and treatment of CRS include the IL-1 receptor antagonist anakinra, IL-6 antagonist siltuximab, and the IFN-γ–blocking antibody emapalumab. However, these agents have demonstrated limited clinical effectiveness in comparison to corticosteroids and tocilizumab (Jain et al, 2023).
Immune effector cell-associated neurotoxicity syndrome
Immune effector cell–associated neurotoxicity syndrome (ICANS), is another common and potentially life-threatening complication that is associated with effector cell-engaging therapies such as CAR T-cell therapy (Lee et al, 2019). ICANS is a condition that is used to describe a pathologic process involving the central nervous system which manifests as delirium, headache, aphasia, dysgraphia (impaired handwriting), concentration impairment, agitation, tremor and cognitive disturbance. In severe cases, it can lead to lethargy, encephalopathy, obtundation, seizures, cerebral oedema, and even death (Zahid et al, 2020).
The pathophysiology of ICANS is thought to involve endothelial activation and massive capillary leakage that disrupts the blood-brain barrier and impairs its permeability, leading to a massive influx of systemic cytokines into the cerebrospinal fluid (Sterner and Sterner, 2022). The resulting loss of vascular integrity leads to pericyte stress, vascular damage, multifocal brain haemorrhages and cerebral oedema, which manifests as neurotoxicity (Gust et al, 2017). Other proposed mechanisms include elevated levels of excitatory neurotransmitters such as glutamate and quinolinic acid in the cerebrospinal fluid, which leads to a lowering in the seizure threshold (Santomasso et al, 2018), and macrophage infiltration into the subarachnoid space, leading to multifocal brain meningeal thickening (Norelli et al, 2018).
The incidence of ICANS resulting from CAR T-cell therapy ranges from 2% to 64% (Xiao et al, 2021), with reported mortality rates varying between 6% and 72% (Sheth and Gauthier, 2021). The severity of ICANS is assessed according to the ASTCT consensus guidelines (Lee et al, 2019), which categorise symptoms based on five neurotoxicity domains in the immune effector cell encephalopathy (ICE) score, level of consciousness, seizure, motor findings, and elevated intracranial pressure or cerebral oedema (Lee et al, 2019) (Table 2). Higher scores reflect a more severe event and a less favourable outcome.
| Neurotoxicity domain | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|
| Immune effector cell encephalopathy (ICE) score* | 7–9 | 3–6 | 0–2 | 0 (patient is unarousable and unable to perform ICE) |
| Depressed level of consciousness† | Awakens spontaneously | Awakens to voice | Awakens only to tactile stimulus | Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma |
| Seizure | n/a | n/a | Any clinical seizure, focal or generalised, that resolves rapidly or non-convulsive seizures on EEG that resolve with intervention | Life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between |
| Motor findings‡ | n/a | n/a | n/a | Deep focal motor weakness such as hemiparesis or paraparesis |
| Elevated increased intracranial pressure/cerebral oedema | n/a | n/a | Focal/local oedema on neuroimaging§ | Diffuse cerebral oedema on neuroimaging; decerebrate or decorticate posturing; or sixth cranial nerve palsy; or papilloedema; or Cushing's triad |
A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable
Currently, there is no definitive treatment for ICANS. However, pre-emptive administration of corticosteroids (such as dexamethasone and methylprednisolone), and the IL-6 antagonist tocilizumab, have been trialled as potential interventions to reduce the incidence and severity of ICANS in the clinical setting (Jain et al, 2023). For patients scoring 2 or higher on the ICE scale, high-dose steroids are the recommended course of therapy (Rees, 2022).
Early ICU admission and supportive care are essential to treat symptoms of ICANS. Close monitoring of neurological signs and symptoms is crucial, as early indicators of neurotoxicity such as inattention, disorientation, impaired concentration, dysgraphia, difficulty naming objects (dysphasia) or apraxia, can be subtle or may have an insidious onset. Other neurologic symptoms such as speech changes or facial automatisms and twitching may resemble stroke or complex partial seizures, complicating the diagnosis of ICANS. Severe neurotoxicity usually begins with expressive aphasia, paraphasic errors and verbal perseverations before progressing into somnolence, myoclonus, obtundation, coma and seizures (Santotomasso et al, 2018).
Management of ICANS is primarily supportive and is aimed at maintaining neuroprotection and the prevention of life-threatening complications. Patients with higher ASTCT grades (ie grade >2) should be transferred to an intensive care setting to facilitate close observation and early institution of life-saving interventions. The emergence of new neurological deficit necessitates an urgent neurologist referral and imaging studies (such as CT or MRI) to determine aetiology. For patients experiencing new-onset seizures, anticonvulsants such as levetiracetam and benzodiazepines are commonly used, with phenobarbital reserved for cases of status epilepticus. In the presence of a focal or global deficit, an EEG, brain MRI, lumbar puncture or spine MRI may be considered to help establish a diagnosis. Intubation and mechanical ventilation may be warranted to protect the airway and prevent aspiration. Patients with signs of increased intracranial pressure (ICP) such as papilloedema may benefit from acetazolamide, hyperosmolar therapies (mannitol or hypertonic saline), invasive ICP monitoring or neurosurgical interventions. High-grade ICANS is a poor prognostic sign and can lead to death if not addressed promptly.
Prospects, promises and pitfalls of CAR T-cell therapy
As of December 2023, there are six CAR T-cell products that are approved for administration by the US FDA and EU EMA (Table 3) (Bellino et al, 2023). These CAR T-cell products are licensed for the treatment of B-cell ALL, various forms of B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma.
| Drug and manufacturer | Indication | Reference |
|---|---|---|
| Tisagenlecleucel (Kymriah®, Novartis) | Treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in people aged up to 25 years |
NICE Technology appraisal guidance TA554, 21 December 2018 (NICE, 2018) |
| Axicabtagene ciloleucel (Yescarta®, Kite Pharma/Gilead) | Treatment of diffuse large B-cell lymphoma in adults who have relapsed within 12 months or refractory to first-line chemoimmunotherapy |
NICE Technology appraisal guidance TA895, 7 June 2023 (NICE, 2023a) |
| Brexucabtagene autoleucel (Tecartus®, Kite Pharma/Gilead) | An option for relapsed or refractory mantle cell lymphoma in adults who have previously had a Bruton's tyrosine kinase (BTK) inhibitor |
NICE Technology appraisal guidance TA677, 24 February 2021 (NICE, 2021) |
| Lisocabtagene maraleucel (Breyanzi®, Juno Therapeutics/Bristol Myers Squibb) | Treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL): |
EMA/164279/2023, 8 April 2022 (EMA, 2023) |
| Idecabtagene vicleucel (Abecma®, Bluebird Bio/Bristol Myers Squibb) | Treatment of adults with relapsed or refractory multiple myeloma who have received at least 2 prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and whose disease has worsened since the preceding treatment | EMA/52692/2024, 3 April 2024 (EMA, 2024) |
| Ciltacabtagene autoleucel (Carvykti®, Janssen/Johnson & Johnson) | Treatment of adults with relapsed or refractory multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and whose disease has worsened since the preceding treatment | EMA/233731/2022, 13 June 2022 (EMA, 2022b) |
CAR T-cell therapy as a form of adoptive therapy is not only revolutionary in terms of outcomes, but provides a new direction and target in the delivery of precision medicine in the NHS. Stringent requirements were established to ensure that NHS providers are adequately prepared to deliver CAR T-cell therapy, including the development of the necessary infrastructure to support clinical safety, regulatory compliance, and adherence to the quality and safety standards mandated by drug manufacturers and life science companies (Williamson, 2019). Comprehensive policies, procedures, and quality standards have been meticulously defined and implemented, along with the establishment of appropriate systems, facilities and care pathways, to ensure the effective delivery of the service and mitigate foreseeable risks (Advanced Therapy Treatment Centre Network, 2023).
Given the substantial initial costs associated with CAR T-cell therapy, the number of NHS and JACIE-accredited centres capable of delivering this treatment remains limited. As of December 2024, there were 21 NHS centres in the UK that provide CAR T-cell therapy for the treatment of ALL, large B-cell lymphoma and mantle cell lymphoma (NHS England, 2024). The limited number of patients who have recently undergone this therapy presents challenges in evaluating long-term outcomes and potential late complications, which are yet to be fully identified. Comprehensive population-based studies and long-term outcome data are critical for informing regulators and healthcare providers about the feasibility of expanding this therapy to a broader patient population. Should CAR T-cell therapy prove successful, it is imperative that existing centres increase their capacity, while encouraging new centres to develop the necessary infrastructure to support its broader implementation. As noted by the Institute of Cancer Research, robust political will and significant reforms are essential to advancing these innovations and ensuring their accessibility to the patients most likely to benefit from such interventions (Hastings, 2018).
The delivery of CAR T-cell therapy requires nurses, clinicians and other health professionals with adequate training, competency and experience in immunotherapy and management of its complications. The clinical care of patients receiving CAR T-cell therapy requires a multidisciplinary approach, and nurses may encounter this cohort of patients in an outpatient, ambulatory or inpatient setting. It is crucial for facilities delivering CAR T-cell therapy to provide nurses with practice framework guidelines and essential training to look after patients receiving CAR T-cell products both in the short and long term. As prompt detection of complications is crucial in improving outcomes and preventing deterioration, nurses working in haematology-oncology units must be skilled and confident in early diagnosis and referral to outreach or medical teams. Systems and procedures must be in place to facilitate swift transfer to the intensive care setting and institute life-saving interventions (such as mechanical ventilation or initiating vasopressor support) or commence complex monitoring (advanced haemodynamic monitoring, ICP monitoring). Involvement of other health professionals is also crucial (such as intensivists, surgeons, physiotherapists, nutritionists, dietitians, psychologists, counsellors, palliative care services) and regular multidisciplinary meetings should be implemented to guide therapy direction, trajectory and goals.
One of the principal barriers to the widespread adoption of CAR T-cell therapy is its prohibitive cost. At its full price, tisagenlecleucel (Kymriah) costs approximately £282 000, axicabtagene-ciloleucel (Yescarta) is priced at around £208 451 (Litvinova et al, 2024) and brexucabtagene autoleucel (Tecartus) costs around £316 089 (Shah et al, 2022). In response, NHS England has negotiated with life sciences manufacturers to secure these therapies at a discounted rate, making them available to eligible patients at no cost through the NHS (Williamson, 2019).
Economic and healthcare utilisation studies of CAR T-cell therapy in the USA shows that the average cost of CAR T-cell administration within a hospital inpatient setting is approximately US$454 611 (£359 974) (Lyman et al, 2020). This figure can rise to as high as US$500 000 (£395 914) for patients who develop significant complications (Hernandez et al, 2018). Cost-effectiveness analyses of CAR T-cell therapies are limited by lack of comprehensive data on long-term survival, response rates and overall effectiveness, although some anecdotal evidence show relatively favourable results (Choi et al, 2022).
A recently published report showed that around 1087 CAR T-cell clinical trials are currently under way, which may help drive down production costs and reduce therapy prices in the future (Wang et al, 2023b). At present, however, with the current limited options, affordability remains a critical issue, particularly within the context of the NHS, whose budget heavily relies on the taxpayers’ contributions.
Conclusion
The landscape of oncologic management is undergoing rapid transformation, with CAR T-cell therapy emerging as one of the most promising new treatments that have successfully transitioned from clinical trials to mainstream clinical practice. Despite its high cost and associated risks, CAR T-cell therapy offers significant potential and a ‘ray of hope’ to patients (Marofi et al, 2021) in the treatment of refractory, relapsing and intractable haematologic cancers, which claim the lives of approximately 9000 individuals in the UK annually – comprising around 4800 deaths from leukaemia and 4900 from non-Hodgkin lymphoma, based on data between 2017 and 2019 (Cancer Research UK, 2022).
Although the introduction of CAR T-cell therapy in the NHS is expected to accelerate the broader adoption of adoptive effector therapies as a standard of care for these patient groups, significant challenges remain. Policies and procedures governing NHS organisations that provide these services need to be strengthened and streamlined, with a particular focus on capacity-building and the training of clinical staff responsible for patient care. Additionally, new standards of care and clinical pathways must be developed to optimise patient outcomes and mitigate associated risks. Encouraging and expanding academic, clinical and industrial partnerships is also essential to advancing research and development, which could ultimately lead to a reduction in costs (Wang et al, 2023b).
Debates continue regarding whether the benefits of CAR T-cell therapies justify their burdens and costs (Choi et al, 2022), particularly within the context of the NHS, where services are publicly funded by taxpayers. The risks and complications associated with CAR T-cell therapy are considerable, and recent studies indicate that, despite its relative success, treatment failure rates remain significant – for instance, a meta-analysis reported a 1-year pooled treatment relapse prevalence of 24% (Zinzi et al, 2023). In response to these challenges, newer adoptive immunotherapies, such as CAR-natural killer, CAR-macrophage, and CAR-γδ T-cells, are being developed, each aiming to offer improved effectiveness with reduced risks (Zhang et al, 2023). Future research should prioritise the development of these safer therapies, focusing not only on enhancing disease targeting but also on improving outcomes and quality of life for these vulnerable patient populations.