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Chimeric antigen receptor-T (CAR-T) cell therapy is an evolving treatment entity used to treat relapsed/refractory cancers. It involves genetically modifying autologous or allogeneic T cells to express Chimeric Antigen Receptor (CAR) proteins that target specific cancer cells. Despite promising outcomes, these cells attack normal tissue cells expressing similar proteins on their surfaces. This cross-reactivity results in adverse events (AEs), leading to substantial mortality and morbidity. This activity reviews the evaluation and treatment of CAR-T toxicity and highlights the role of interprofessional teams in evaluating and treating patients with these AEs. Objectives: Identify the most common adverse events associated with CAR-T cell therapy. Describe the pathophysiology for developing CAR-T AEs, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Summarize management for CRS and ICANS. Explain the importance of a multidisciplinary team approach to prevent morbidity and mortality of CAR-T-related toxicities. Access free multiple choice questions on this topic.

Chimeric antigen receptor-T (CAR-T) cell therapy is a type of genetically modified immunotherapy that is directed at cancer cells. The method involves using an individual's own T-cells (or donor cells in allogeneic CART), transduced with gene encodes ex vivo, then introduced to the patient.[1] CAR-T has changed the treatment paradigm for hematological malignancies, such as B-cell lymphomas and multiple myeloma, and continues to be a promising approach for many other malignancies, including solid tumors.[2][3][4][5] Clusters of differentiation-19 (CD-19), a B cell surface marker, -directed CAR-T cells show encouraging outcomes in a variety of malignancies, including pediatric and B-cell acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL). The first approved CAR-T therapy targeting CD-19, tisagenlecleucel (tisa-cel, ELIANA), was initially approved by the Food and Drug Administration (FDA) for patients with ALL in 2017, and later diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (JULIET).[6][7][8] Around the same time, axicabtagene ciloleucel (axi-cel, ZUMA-1) gained approval for relapsed/refractory (R/R) DLBCL and later for R/R follicular lymphoma.[9][10] Since then, more agents such as lisocabtagene maraleucel (liso-cel) have made their way onto the market, demonstrating better tolerance.[11] Later, brexucabtagene autoleucel was approved for R/R mantle cell lymphoma (MCL).[12] More recently, anti-B-cell Maturation Antigen (BCMA) CAR-T, idecabtagene vicleucel (ide-cel, KarMMa), and ciltacabtagene autoleucel (cilta-cel, CARTITUDE-1) have been approved for R/R multiple myeloma.[3][4] Despite the current success rate of CAR-T therapy, it comes with the caveat of significant toxicities. The most common adverse events (AEs) of CAR-T therapy, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain barriers to the use of CAR-T cell therapy. Other AEs, such as cytopenia,s, infections, tumor lysis syndrome (TLS), acute anaphylaxis, etc., are also challenging.[13] Now that cellular therapy is making its way to earlier lines of the treatment paradigm, these challenges have become even more relevant.[14][15]

The exact mechanism of CRS is not well understood. CRS is a systemic inflammatory response that occurs during the CAR-T activation and expansion in the human body.[16] It is thought to be related to the cytokines secreted during the tumor and immune effector cell interaction, including tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which then activate monocytes and macrophages to release cytokines such as interleukin-1 (IL-1), and IL-6.[17] ICANS is thought to be related to myeloid cell activation, including granulocyte-macrophage colony-stimulating factor (GM-CSF) mediated stimulation of monocytes after CAR-T and monocyte-derived IL-1 and IL-6. [18][19] The costimulatory domain is a component of CAR-T necessary for T cell activation and expansion of the CAR-T cells.[20] CAR-T therapies that activate 4-1BB (tisa-cel, liso-cel) costimulatory domain instead of CD28 (axi-cel) have exhibited slower expansion, thus prolonging the persistence of CAR-T cells and later CRS onset.[21][22] While this has assisted in bringing these therapies outpatient, logistics, reimbursement, and managing CAR-T therapy-related AEs are the major challenges healthcare providers face.[23]

CAR-T-related toxicity occurs with varying frequency depending on factors discussed later. CRS is the most common type of toxicity associated with CAR-T therapy, followed by ICANS. Cytokine Release Syndrome (CRS) CRS is considered a predominantly reversible complication of CAR-T therapy, with an incidence of occurrence in 42 to 100% of the patients. It presents with varying severity, with 0 to 46% of patients exhibiting features of severe CRS and from 0 to 9.1% of cases progressing to fatal outcomes.[24] Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Similar to CRS, ICANS presents in most patients after CAR-T infusions as a reversible complication. It occurs less frequently and is often delayed compared to CRS, with the incidence ranging between 3 and 64% and 0 to 54% of cases exhibiting signs of severe illness.[25]

Cytokine Release Syndrome (CRS) CRS is the most common type of toxicity following CAR-T therapy. It is a multi-systemic inflammatory response caused by cytokines released following the infusion of CAR-T cells that can lead to multiorgan dysfunction. The onset of symptoms usually occurs during the first week after CAR-T cell infusion, with a typical duration of 7 to 8 days.[26][27] Multiple risk factors for CRS include high disease burden, a high number of administered CAR-T cells, the high peak of CAR-T cell expansion, thrombocytopenia, endothelial activation before CAR-T infusion, and lymphodepletion therapy with fludarabine and cyclophosphamide.[27] Studies have suggested that disease characteristics such as tumor burden, Eastern Cooperative Oncology Group (ECOG) performance status, ferritin, lactate dehydrogenase (LDH), and C reactive protein (CRP) levels prior to CAR-T can be used as predictors of the onset of CRS and ICANS, thus guiding the outcomes of CAR-T.[28][28] Pathophysiology CRS is thought to be related to the production of inflammatory cytokines by CAR-T, e.g., TNF-a, IFN-γ, IL-2, IL-8, IL-10, and GM-CSF following interaction with corresponding target cells.[17] Following that, inflammation recruits and provokes bystander immune cells, e.g., macrophages, monocytes, dendritic cells (DC), and other T cells. Eventually, it potentiates the immune response by releasing IL-1 and IL-6 as well as nitric oxide. This hyperactivated inflammatory response provokes the endothelium, which further releases IL-6. This destabilizes membrane stability, resulting in capillary membrane leakage, hemodynamic instability, and consumptive coagulopathy. Clinical Features CRS typically presents with constitutional symptoms such as a fever, fatigue, myalgia, arthralgia, rigors, or anorexia. It can rapidly progress to tachycardia, hypotension requiring vasopressors and intensive care unit (ICU) care, tachypnea, and hypoxia. Eventually, it can lead to coagulopathy, capillary leak, respiratory failure, shock, and multiple organ failure. Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)

CRS typically presents with constitutional symptoms such as a fever, fatigue, myalgia, arthralgia, rigors, or anorexia. It can rapidly progress to tachycardia, hypotension requiring vasopressors and intensive care unit (ICU) care, tachypnea, and hypoxia. Eventually, it can lead to coagulopathy, capillary leak, respiratory failure, shock, and multiple organ failure. Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) It is a form of clinical and neuropsychiatric disease manifestation that occurs within days to 2-3 weeks following CAR-T therapy administration.[29] The risk factors for ICANS include the presence of CRS, pre-existing neurologic dysfunction, high disease burden, elevated LDH, thrombocytopenia, elevated ferritin within 72 hours after CAR-T cell administration, chimeric antigen receptor (CAR) design such as CD28 costimulatory domain, certain hinge, transmembrane CAR domains, and lymphodepletion therapy with fludarabine and cyclophosphamide.[29] Pathophysiology The pathophysiology behind ICANS is not well studied. Theories include CNS trafficking of CAR-T cells and endothelial disruption within the blood-brain barrier. Moreover, myeloid cell activation in the CNS with the secretion of IL-1 and IL-6 by monocytes, GM-CSF-mediated stimulation of monocytes after CART, elevated levels of IL-15, and N-methyl-D-aspartate (NMDA) receptor agonists (e.g., glutamate and quinolinic acid) have all been suggested to cause ICANS.[18][19] Cytopenias Cytopenias are very frequent following CAR-T cell therapy, the most common being neutropenia. They occur in about 20-40% of patients and can last beyond 30 days after administration.[30][31] According to a systematic analysis following CD-19 CAR-T therapy, the rates of all grade anemia, thrombocytopenia, and neutropenia, were 65%, 55%, and 78%, respectively. Age, gender, disease, number of prior lines of therapy, and the target and costimulatory domain have been noted to influence the incidence of cytopenias following CAR-T therapy.[32] Tumor Lysis Syndrome (TLS) TLS can be a life-threatening condition leading to arrhythmias and renal failure. It usually occurs due to cell depletion following chemotherapy but can occur as a direct effect following CAR T-cell therapy.[33] It can be related to elevated levels of serum creatinine and severe CRS.[34] Anaphylaxis and Immunogenicity

Tumor Lysis Syndrome (TLS) TLS can be a life-threatening condition leading to arrhythmias and renal failure. It usually occurs due to cell depletion following chemotherapy but can occur as a direct effect following CAR T-cell therapy.[33] It can be related to elevated levels of serum creatinine and severe CRS.[34] Anaphylaxis and Immunogenicity CAR-T cells involve the addition of non-human products that renders a risk for allergic reactions. Anaphylaxis is rather uncommon and is reported only with repeated CAR-T infusions. Additionally, anti-murine antibodies against CD-19 have been detected prior to CAR-T cell infusion. Fully human-containing CAR-T cells are under clinical trials.[35] Hypogammaglobulinema due to B-Cell Aplasia B-cell aplasia with hypogammaglobulinemia is an expected AE associated with CAR-T therapy.[36][37] Hypogammaglobulinemia can be delayed and increases the risk of infections.[38] B-cell aplasia could last for up to 5 years, with longer aplasia usually being noticed after comprising 4-1BB as a costimulatory domain. Thus it can be used as a biomarker to assess CAR-T cell persistence.[39][38][40] Infections Multiple etiologies can explain recurrent infections, including underlying disease, cytotoxic treatment, neutropenia, hypogammaglobinemia, treatment for CRS and ICANS, and the CAR-T itself. In addition, patients with an absolute neutrophil count (ANC) <500 cells/mm3 receiving higher doses of CAR-T therapy administration carry a higher risk than other patients.[30] Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) Hemophagocytic lymphohistiocytosis (HLH) was reported in around 1% of patients receiving CAR-T cells.[41] It was unclear whether HLH/MAS represents the end point of CRS until the ASTCT grading guidelines excluded HLH/MAS from the definition of CRS, and then the diagnostic criteria were identified (see table below).[41] Table Diagnostic Criteria of Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [adapted from criteria proposed by the CARTOX Working Group] Ferritin >10,000 ng/ml during CRS Secondary Malignancies Secondary malignancies after CAR-T are primarily related to lymphodepletion chemotherapy, including myelodysplastic syndrome, acute myeloid leukemia, etc.[42][43] Graft-Versus-Host Disease (GVHD)

Diagnostic Criteria of Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [adapted from criteria proposed by the CARTOX Working Group] Ferritin >10,000 ng/ml during CRS Secondary Malignancies Secondary malignancies after CAR-T are primarily related to lymphodepletion chemotherapy, including myelodysplastic syndrome, acute myeloid leukemia, etc.[42][43] Graft-Versus-Host Disease (GVHD) Patients receiving allogeneic CAR-T cells from donors carry a risk of developing mild acute GVHD or slow worsening of previously existing chronic GVHD, though this has only rarely been reported.[34][44]

Healthcare professionals caring for patients receiving commercial CAR-T products must complete product-specific Risk Evaluation and Mitigation Strategy (REMS) training.[45][46][47] Nurses caring for these patients are educated to recognize CAR-T AEs, especially CRS and ICANS.[46] Every CAR-T center has institutional guidelines to evaluate the patients for related toxicities, depending on whether the CAR-T product was infused in an inpatient or outpatient setting. Generally, in an outpatient setting, patients are evaluated once daily for both CRS and ICANS-related features for at least 14 days and up to 30 days post-infusion. If the CAR-T therapy is administered inpatient, vitals are typically assessed every 4 hours; the ICE score is at least once a day, with a daily comprehensive physical exam and blood work including complete blood count (CBC) and complete metabolic panel (CMP).[41] If a patient is admitted with an AE such as CRS, vital signs are checked more frequently, ideally every 2-4 hours, immune effector cell-associated encephalopathy (ICE) score is evaluated at least once a day and up to every 8 hours, and blood work including CBC, CMP, and other relevant tests are done once to twice daily.[41][48] Most centers alert neurology service for a neurological evaluation of the patient before the CAR-T administration. However, in case of a suspected or confirmed ICANS-related toxicity, a neurological exam is performed at least 4-6 hourly or more frequently if a decline in the neurological status is noted.[49] Further neurological investigations, including neuroimaging, electroencephalogram (EEG), etc., are performed if there is a concern for ICANS.[41]

Toxicities related to CAR-T cell therapy are diverse and still poorly understood. The evaluation of CAR-T-associated toxicities and their severity is based on clinical symptoms and signs, which are further aided by laboratory biomarkers and/or radiological findings. CRS: It is a clinical diagnosis and usually presents with varying degrees of fever, tachycardia, hypotension, hypoxia, nausea, vomiting, etc. The vital signs are assessed frequently, depending on the institutional policies, with most centers mandating reevaluation every 4 hours for grades 1 and 2 and 1 to 2 hourly evaluations for grades 3 and 4 CRS.[41][48] Useful laboratory evaluation for CRS involves performing a CBC, renal and liver function test, coagulation profile, LDH, serum ferritin, IL-6, and CRP. These biomarkers are performed serially to determine the severity and response to the treatment. Some have also postulated checking IL-5,  IL-13, TNF-a, and IFN-γ levels.[50][51] ICANS: Like CRS, ICANS is diagnosed based on clinical symptoms, including headache, impaired attention and consciousness, lethargy, agitation, hallucinations, tremors, aphasia, encephalopathy, and seizures.[52] As discussed in detail below, the grading and surveillance of neurotoxicity are based on the ICE criteria (which has replaced the CARTOX-10 criteria to include more objectivity in the neurotoxicity grading).[50][53][28] Laboratory evaluation of ICANS includes biomarkers similar to CRS in addition to a lumbar puncture to analyze cerebrospinal fluid, neuroimaging, and EEG to determine the extent of damage from ICANS and rule out other organic factors and/or sinister causes, including but not limited to infections.[41]

Here, we review the toxicities caused by CAR-T cell therapy and summarize the clinical findings, grades, and management of the most relevant adverse events associated with CAR-T cell therapy. The toxicity of CAR-T remains challenging. However, numerous safety measures have been implemented in clinical trials.[27] Standardized protocols need to be developed, including universal guidelines for managing CRS and ICANs and the safe administration of outpatient CAR-T therapy.[54] Management of CRS and ICANS requires frequent assessment and grading several times a day in addition to monitoring inflammatory markers such as ferritin and CRP. Aggressive supportive care is the cornerstone of managing all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. IL-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. For FDA-approved CAR-T cell products, REMS requires prompt availability of at least two doses of tocilizumab per patient that can be administered within two hours of CAR-T infusion.[55] Corticosteroids should only be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the activity of the CAR-T cells.[56] Given the potential of corticosteroids to limit CAR-T cell proliferation and expansion, they should not be permitted starting on the first day of lymphodepletion chemotherapy, including as antiemetics.[57] Cytokine Release Syndrome (CRS) Grading and management of CRS are derived from the American Society for Transplantation and Cellular Therapy (ASTCT) consensus guidelines for CRS grading.[28][58][59] Table Symtpoms require symptomatic treatment only Fever, nausea, fatigue, headache, myalgia, malaise, etc., but no hypotension or hypoxia. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) The grading and proposed management of ICANS are according to and adapted from the ASTCT consensus guidelines for ICANS grading.[28][53] Table Immune effector cell-associated encephalopathy (ICE) score 7-9. Awakens spontaneously. Immune effector cell-associated encephalopathy (ICE) assessment adapted from ASTCT grading consensus guidelines:[28] Table ICE Parameter Task CRS and ICANS Refractory to the Above Treatment

The grading and proposed management of ICANS are according to and adapted from the ASTCT consensus guidelines for ICANS grading.[28][53] Table Immune effector cell-associated encephalopathy (ICE) score 7-9. Awakens spontaneously. Immune effector cell-associated encephalopathy (ICE) assessment adapted from ASTCT grading consensus guidelines:[28] Table ICE Parameter Task CRS and ICANS Refractory to the Above Treatment If despite the use of tocilizumab and corticosteroids, patients with CRS and ICANS continue to worsen, siltuximab, a monoclonal antibody, binds to  IL-6, thus preventing it from binding to the IL-6 receptors.[60] Another alternative is Anakinra, which is an IL-1 receptor that shows activity in CRS and ICANS that is refractory to corticosteroids and tocilizumab.[61] Given that IL-1 precedes IL-6 production, it can be used to prevent CRS and ICANS. However, further studies are still under investigation.[62] Cytopenias Mostly, cytopenias resolve over time. Bone marrow biopsy is recommended in patients with prolonged or delayed cytopenias to evaluate for secondary bone marrow malignancy.[63] Anemia and thrombocytopenia are managed through the replacement of erythrocytes and platelets. Granulocyte colony-stimulating factor (G-CSF) is used to manage neutropenia and should be strongly recommended in patients with prolonged neutropenia. Anecdotally, persistent refractory cytopenia after CAR-T has been treated by the infusion of autologous or allogeneic stem cells.[32][63] Tumor Lysis Syndrome Management involves frequent hydration and the use of uric acid-lowering agents (allopurinol, rasburicase, and febuxostat) as per the standard guidelines for chemotherapy.[33][64] Hypogammaglobulinema Due to B-Cell Aplasia Long-term follow-up is essential to assess the need for IgG replacement.[65] In pediatric patients, intravenous immunoglobulin (IVIG) replacement is typically given.[66] In adults, antibody-secreting CD19-negative cells resembling memory plasma cells that show basic humoral immune function despite CAR-T cell treatment have been noted. Hence, in adults, IVIG is usually given at IgG levels ≥ 400 mg/dl or in patients with severe or recurrent infections, usually at a dose of 400 to 600 mg/kg every 3 to 4 weeks.[66][38] Infections

Long-term follow-up is essential to assess the need for IgG replacement.[65] In pediatric patients, intravenous immunoglobulin (IVIG) replacement is typically given.[66] In adults, antibody-secreting CD19-negative cells resembling memory plasma cells that show basic humoral immune function despite CAR-T cell treatment have been noted. Hence, in adults, IVIG is usually given at IgG levels ≥ 400 mg/dl or in patients with severe or recurrent infections, usually at a dose of 400 to 600 mg/kg every 3 to 4 weeks.[66][38] Infections Patients with fevers and neutropenia should have blood cultures drawn and broad-spectrum antibiotics initiated.[52] Antimicrobial prophylaxis is majorly extrapolated from that of hematopoietic stem cell transplants (HSCT). This includes antimicrobials, such as acyclovir or valacyclovir, for herpes simplex virus (HSV), and varicella zoster (VZV), starting prior to the conditioning chemotherapy continuing up to 1-year following CAR-T therapy.[30][52] Trimethoprim-sulfamethoxazole or alternative agents are recommended for pneumocystis jirovecii (PJP) starting before conditioning chemotherapy and is usually continued until CD4 reaches more than 200/ml.[30][32][52] Antifungal prophylaxis should be considered in those at high risk, such as prolonged steroid exposure, or in patients within patients with prolonged (>14 days) or severe (ANC <0.5 × 10/l) neutropenia.[30] Hemophagocytic Lymphohistiocytosis Treatment usually involves corticosteroids and tocilizumab if co-existent with CRS. In refractory cases or if independent of CRS, treatment with etoposide and intrathecal methotrexate or cytarabine has been suggested. Additionally, anakinra has also been proposed but needs further evaluation.[67]

Differential diagnoses for CRS are mainly related to its clinical manifestations and laboratory findings, such as fever and/or hypoxia and hypotension, elevated CRP, ferritin, and IL-6 levels.[68] These include Infection/sepsis, anaphylactic reactions/shock, heart failure, thromboembolism, malignancy relapse/refractoriness, TLS, and HLH unrelated to CAR-T toxicity.[69][70][71] These patients are usually required to undergo extensive evaluation and investigations to rule out other causes and often require empirical treatments until proven otherwise. ICANS can be frequently confused with uncommon viral infections, stroke, chemotherapy-related toxicity, and the CNS involvement of malignancy.[72]

CRS: It is a reversible complication, mostly symptoms resolving within 2 to 6 weeks. Mortality can be observed in 0 to 9.1% of cases.[25][24] However, the majority of trials have reported <1% fatal outcomes.[28] ICANS: A vast majority of cases of neurotoxicity associated with CART therapy show symptom resolution within 3-8 weeks.[73][74] With early and aggressive management, even high-grade CRS is considered reversible.

While, in most instances, CAR-T complications are reversible, occasionally, they can lead to death or irreversible organ damage.[25] Neuropsychiatric AEs such as anxiety, depression, or cognitive difficulty have been reported in long-term survivors of CAR-T, up to 37.5% in one study.[75]

Frequent monitoring, clear instructions for patients and caregivers, and a robust on-call system are essential post-CAR-T. Patients and caregivers should be provided with after-hours contact information, clear instructions for monitoring symptoms and vital signs, and when to present to the hospital.[57] Patients need to be provided with a product-specific wallet card identifying their reception of a CAR T-cell product and giving information about the managing oncologist. They will need to show their wallet card if and when they present for evaluation of symptoms, especially if they arrive at a hospital or emergency department (ED) outside of the CAR-T therapy programs.[46] Caregiver support throughout the process of CAR-T and after is critical. The need for a 24-hour caregiver for at least four weeks and staying close to the center after treatment should be emphasized.[76] Caregivers should be included from the start, from informed consenting to teaching, clinic visit, and after discharge.

Cancer immunotherapy has greatly advanced in recent years, with CAR-T cells emerging as an innovative technology that harnesses the immune system to combat malignant diseases. An interprofessional team is needed to recognize and appropriately manage CAR-T AEs, including but not limited to neurology, critical care, and infectious diseases subspecialties. Most centers alert the neurology team for a neurological evaluation of the patient prior to the CAR-T administration. Efforts should be aimed at providing accommodation to the patients traveling far from home for CAR-T and assisting with out-of-pocket costs.[77] Patient prerequisites that are fundamental for managing complications of HSCT post-discharge are also relevant to successful CAR-T, including socioeconomic and caregiver support and patient staying within a 1-hour transportation distance from the hospital for at least four weeks post-infusion.[46] Various centers have devised comprehensive protocols to monitor patients closely, ensure multidisciplinary coordination, and quick evaluation of the patients in either the clinic or ED for any AEs, including fever, CRS, and ICANs.[47][41]