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Axicabtagene ciloleucel

Axicabtagene ciloleucel, sold under the brand name Yescarta, is a CD19-directed genetically modified autologous T cell immunotherapy approved for the treatment of adults with certain relapsed or refractory B-cell non-Hodgkin lymphomas.^[1] It consists of a patient's own T cells that are collected via leukapheresis, genetically engineered ex vivo using a retroviral vector to express a chimeric antigen receptor (CAR) targeting the CD19 antigen on B cells, expanded in culture, and then reinfused into the patient following lymphodepleting chemotherapy.^[1] Upon infusion, the modified CAR T cells recognize and bind to CD19-expressing malignant B cells, triggering T cell activation, proliferation, cytokine release, and targeted cytotoxicity to eliminate cancer cells while also depleting normal CD19-positive B cells.^[1] Developed by Kite Pharma (a subsidiary of Gilead Sciences), axicabtagene ciloleucel received its initial U.S. Food and Drug Administration (FDA) approval on October 18, 2017, for adult patients with relapsed or refractory large B-cell lymphoma (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma) after two or more lines of systemic therapy.^[2] The therapy's indications were expanded on March 5, 2021, with accelerated approval for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy, based on objective response rates from the ZUMA-5 trial (91% overall response rate, including 60% complete remission).^[3]^[1] Further expansion occurred on April 1, 2022, approving its use as second-line therapy for large B-cell lymphoma refractory to or relapsing within 12 months of first-line chemoimmunotherapy, supported by the ZUMA-7 trial demonstrating superior event-free survival (median 8.3 months vs. 2.0 months with standard therapy) and overall response rates (83%, with 65% complete remission).^[4]^[1] It is not indicated for primary central nervous system lymphoma.^[1] The therapy is administered as a single intravenous infusion of 2 × 10^6 CAR-positive viable T cells per kg of body weight, preceded by fludarabine and cyclophosphamide for lymphodepletion to enhance CAR T cell expansion and persistence.^[1] Clinical data from pivotal trials like ZUMA-1 for third-line large B-cell lymphoma showed durable responses, with a 72% objective response rate (51% complete remission) and median duration of response of 9.2 months overall (not reached for complete responders).^[1] However, treatment carries significant risks, including cytokine release syndrome (CRS; occurring in 90% of patients, 9% grade ≥3), neurologic toxicities (78% incidence, 25% grade ≥3), serious infections (45%), prolonged cytopenias (39% grade ≥3), and potential secondary malignancies such as T-cell malignancies, necessitating close monitoring in certified treatment centers.^[1] As of June 2025, ongoing updates to the prescribing information reflect continued safety evaluations, emphasizing lifelong surveillance for secondary cancers.^[1]

Medical uses

Indications

Axicabtagene ciloleucel is approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBL), and DLBCL arising from follicular lymphoma, after two or more lines of systemic therapy.^[1] It is also indicated for adults with LBCL that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line treatment.^[4] These approvals are based on clinical data demonstrating objective response rates (ORR) of 72% to 83% and complete remission rates of 51% to 65% in relevant patient populations.^[1] Additionally, axicabtagene ciloleucel received accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy, supported by an ORR of 91% and a complete remission rate of 60%.^[1]^[3] This indication, as a CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, addresses a need in heavily pretreated patients with limited options.^[1] Axicabtagene ciloleucel is not indicated for primary central nervous system lymphoma.^[5]

Administration

Prior to initiating treatment with axicabtagene ciloleucel, patients undergo comprehensive evaluation and eligibility screening to ensure suitability for the therapy. This includes assessing medical history, performance status, and laboratory parameters such as platelet count (>75 × 10⁹/L), along with screening for active infections or inflammatory disorders, which may preclude proceeding. Screen for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.^[1]^[6] The process begins with leukapheresis, a procedure to collect the patient's autologous T cells, typically lasting one day and performed at an authorized center. The collected cells are then sent for ex vivo genetic modification and expansion into the CAR T-cell product. Manufacturing typically takes 3 to 4 weeks, with a median time from leukapheresis to product delivery of 17 to 18 days and to infusion of 24 to 27 days, though delays can occur. If manufacturing delays arise, bridging therapy may be administered between leukapheresis and lymphodepleting chemotherapy to control disease progression, often limited to corticosteroids in cases of high tumor burden, though other options like radiation or chemotherapy have been used in clinical practice without compromising outcomes.^[1]^[6] Lymphodepleting chemotherapy is administered to create an environment conducive to CAR T-cell expansion, consisting of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously daily for 3 days (days -5, -4, and -3 relative to infusion). This regimen begins 5 to 7 days before the scheduled infusion, and product availability must be confirmed prior to starting. Premedication is given 30 to 60 minutes before infusion to mitigate infusion-related reactions, including acetaminophen 650 mg orally and an H1-antihistamine such as diphenhydramine 12.5 to 50 mg intravenously or orally; systemic corticosteroids should be avoided unless required for other reasons.^[1] The target dose of axicabtagene ciloleucel is $2 \times 10^6 chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight, with a maximum of $2 \times 10^8 cells total, delivered as a single intravenous infusion within 30 minutes. The product is thawed at 37°C and administered via a non-leukodepleting filter through a central venous line if possible, with the entire 68 mL bag infused without interruption.^[1] Post-infusion, patients require close monitoring for potential toxicities such as cytokine release syndrome (CRS) and neurologic events. Hospitalization is mandatory for at least 7 days following infusion, with an additional 7 days of availability at a healthcare facility if discharged early, extending to 14 days total if clinically indicated. Tocilizumab, an interleukin-6 receptor antagonist, must be readily available for CRS management, and daily assessments for symptoms are essential. Patients should avoid driving or operating machinery for at least 2 weeks post-infusion.^[1]

Pharmacology

Mechanism of action

Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy designed to target and eliminate malignant B cells expressing the CD19 antigen.^[1] It utilizes the patient's own T cells, which are collected via leukapheresis, isolated, and activated ex vivo before genetic modification.^[1] These T cells are then transduced with a gamma-retroviral vector encoding a chimeric antigen receptor (CAR) specific for the CD19 antigen, a surface protein commonly expressed on B-lineage cells, including those in certain lymphomas.^[7] The modified T cells, now expressing the CAR, are expanded in culture and infused back into the patient following lymphodepleting chemotherapy to enhance their persistence and activity.^[1] The CAR in axicabtagene ciloleucel consists of a single-chain variable fragment (scFv) derived from a murine anti-CD19 antibody, which serves as the extracellular antigen-binding domain.^[7] This scFv is linked via a hinge and transmembrane domain to intracellular signaling domains: the CD28 co-stimulatory domain for enhanced T cell activation and proliferation, and the CD3-zeta (CD3ζ) signaling domain for primary T cell receptor-like signaling.^[1] This second-generation CAR design mimics natural T cell receptor signaling but bypasses the need for major histocompatibility complex presentation, allowing direct recognition of CD19 on target cells.^[7] Upon infusion, the CAR-expressing T cells bind to CD19 on malignant B cells, initiating intracellular signaling cascades that activate the T cells.^[1] This binding triggers T cell proliferation, release of inflammatory cytokines and chemokines, and direct cytotoxic effects, including perforin and granzyme-mediated killing of CD19-positive tumor cells, ultimately leading to B-cell aplasia in responsive patients.^[7] As an intended on-target, off-tumor effect, axicabtagene ciloleucel also eliminates normal CD19-expressing B cells, resulting in hypogammaglobulinemia that requires ongoing immunoglobulin replacement therapy.^[1]

Pharmacodynamics and pharmacokinetics

Axicabtagene ciloleucel exhibits pharmacodynamic effects characterized by rapid in vivo expansion of CAR T cells following infusion, with peak levels typically occurring between 7 and 14 days post-infusion.^[1] This expansion correlates with clinical response, as higher peak CAR T cell levels are observed in responders compared to non-responders.^[1] In patients achieving durable responses, CAR T cells demonstrate sustained persistence, remaining detectable for up to several years in peripheral blood and tissues.^[8] B-cell aplasia serves as a key pharmacodynamic biomarker of activity, reflecting ongoing CAR T cell-mediated targeting of CD19-positive cells, with absence of detectable B cells observed in a majority of evaluable patients at 3 months post-infusion.^[1] The exposure-response relationship for axicabtagene ciloleucel indicates that greater CAR T cell expansion, as measured by higher maximum concentration (C_max) and area under the curve (AUC), is associated with improved objective response rates and response duration.^[9] Representative C_max values range from approximately 20 to 45 cells/μL in responders, with median time to peak around 14 days, while AUC from day 0 to 28 reflects cumulative exposure over the initial expansion phase.^[1] Due to its cellular nature, axicabtagene ciloleucel lacks a traditional half-life; instead, persistence is described by median durations of approximately 180 days, after which levels decline toward baseline but may remain detectable longer in responders.^[9] Several factors influence the pharmacokinetics of axicabtagene ciloleucel, including baseline tumor burden, which inversely correlates with peak expansion and durable responses—lower burdens facilitate greater cell proliferation.^[10] The efficacy of lymphodepleting chemotherapy prior to infusion enhances CAR T cell expansion and persistence by reducing endogenous lymphocytes and creating a favorable microenvironment.^[11] Patient age may also play a role, with potential variations in expansion kinetics observed across age groups, though not always statistically significant.^[12]

Adverse effects

Cytokine release syndrome

Cytokine release syndrome (CRS) is a common and potentially severe adverse effect associated with axicabtagene ciloleucel (axi-cel) therapy, resulting from the rapid activation of engineered T cells following infusion. This systemic inflammatory response arises as the CD19-directed chimeric antigen receptor (CAR) T cells engage tumor antigens, triggering a cascade of cytokine production that can lead to symptoms ranging from mild fever to life-threatening organ dysfunction. In pivotal clinical trials, CRS was the most frequent toxicity observed, highlighting the need for proactive monitoring and intervention in patients receiving axi-cel for relapsed or refractory large B-cell lymphoma.^[1]^[7] The pathophysiology of CRS in axi-cel therapy involves an initial phase of CAR-T cell activation upon recognition of CD19 on malignant B cells, leading to the release of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This early activation recruits and stimulates bystander immune cells, particularly macrophages, which amplify the response in a secondary phase by producing high levels of interleukin-6 (IL-6), interleukin-1 (IL-1), and tumor necrosis factor (TNF). The resulting cytokine storm drives endothelial activation, vascular leakage, and systemic inflammation, manifesting as fever, hypotension, and hypoxia; in severe cases, it can progress to multi-organ failure. This process is exacerbated by the potent expansion of axi-cel cells, as observed in trials like ZUMA-1, where peak cytokine levels correlated with symptom severity.^[13]^[7] In the ZUMA-1 pivotal trial, CRS occurred in 94% of patients receiving axi-cel, with 13% experiencing grade 3 or higher events; similar rates were reported in subsequent studies, such as 92% any-grade CRS (11% grade 3 or higher) in ZUMA-7. The median onset is 2 days post-infusion (range 1-12 days), with symptoms typically resolving within 7-8 days (range 2-58 days) following appropriate management. Common manifestations include fever (present in nearly all cases), hypotension (up to 40%), tachycardia, hypoxia (20%), and chills.^[7]^[14]^[1] CRS severity with axi-cel is graded using the Lee criteria (as applied in early trials) or the more recent American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, both of which stratify events from grade 1 (mild, fever without hypotension or hypoxia) to grade 4 (life-threatening, requiring vasopressors). The Lee system emphasizes fever and organ dysfunction, while ASTCT refines grading by isolating fever from other symptoms and incorporating hypoxia thresholds; both facilitate standardized management but may yield slight differences in classification, with ASTCT often resulting in lower severe-grade assignments for the same events.^[1]^[15]^[16] Management of CRS in axi-cel-treated patients prioritizes supportive care for low-grade events (grade 1), including antipyretics and fluids, while escalating to pharmacologic interventions for higher grades. Tocilizumab, an IL-6 receptor antagonist, is recommended for grade 2 or higher CRS at 8 mg/kg intravenously (maximum 800 mg per dose), with repeat dosing every 8 hours if needed, up to a maximum of 3 doses in 24 hours; corticosteroids such as dexamethasone (10 mg IV every 6 hours) are added for persistent or severe symptoms (grade 3-4), and vasopressors are used for hemodynamic instability. In refractory cases, higher-dose methylprednisolone (1 g IV daily for 3 days) or alternative therapies like siltuximab may be considered, with close monitoring in an intensive care setting. Patients must be hospitalized for at least 7 days post-infusion to allow for early detection and intervention.^[17]^[18] Key risk factors for severe CRS with axi-cel include high pretreatment disease burden, which correlates with greater CAR-T cell activation and cytokine release, and early onset of fever (within 1-2 days post-infusion), which predicts escalation to higher grades. Other contributors encompass elevated baseline inflammatory markers and prior allogeneic hematopoietic stem cell transplantation, underscoring the importance of cytoreduction prior to infusion to mitigate risks.^[18]^[7]

Neurologic toxicities

Neurologic toxicities are a significant adverse effect of axicabtagene ciloleucel therapy, occurring in approximately 78% of patients with non-Hodgkin lymphoma, with grade 3 or higher events in 25%.^[1] In pivotal trials such as ZUMA-1 for relapsed or refractory large B-cell lymphoma, the incidence of any-grade neurotoxicity reached 87%, with severe (grade ≥3) cases in 31% of patients.^[1] Common manifestations include encephalopathy (affecting up to 50% of patients), headache (43%), tremor (29%), aphasia (17%), and delirium (15%).^[1] The pathophysiology of these toxicities, often termed immune effector cell-associated neurotoxicity syndrome (ICANS), is multifactorial and likely involves disruption of the blood-brain barrier due to elevated cytokines, direct infiltration of CAR T cells into the central nervous system, or bystander immune effector responses.^[19] Elevated inflammatory markers, such as ferritin and C-reactive protein, correlate with severe ICANS, supporting a role for systemic inflammation in endothelial dysfunction and CNS monocyte migration.^[19] These events frequently follow cytokine release syndrome, which can act as a precursor in up to 64% of neurotoxicity cases across trials.^[1] Neurotoxicities typically emerge with a median onset of 4 to 6 days post-infusion and have a median duration of 15 to 17 days, with nearly all cases (98%) resolving within 8 weeks.^[1] ICANS is differentiated from other neurologic events using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, which employ the 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score to assess cognitive function, alongside evaluations of seizures, motor weakness, and cerebral edema for grading from mild (grade 1) to life-threatening (grade 4).^[20] Management emphasizes supportive care and prompt intervention based on ASTCT grading. Patients receive daily monitoring for at least 7 days post-infusion, with seizure prophylaxis using levetiracetam recommended for grade 2 or higher events.^[1] Corticosteroids, such as dexamethasone (10 mg IV every 6 hours) for grade 2 or methylprednisolone (1 g IV daily) for grades 3-4, are the mainstay for moderate to severe cases, with tapering over several days.^[1] Tocilizumab monotherapy should be avoided for isolated neurotoxicity without concurrent cytokine release syndrome, as it may be ineffective and potentially exacerbate CNS symptoms.^[21]

Secondary malignancies and other risks

Axicabtagene ciloleucel carries a rare risk of secondary T-cell malignancies, including lymphomas and leukemias, potentially arising from insertional mutagenesis induced by the retroviral vector used in its manufacturing. The U.S. Food and Drug Administration (FDA) added a boxed warning in January 2024 for T-cell malignancies following treatment with CD19-directed CAR T-cell therapies, including axicabtagene ciloleucel, based on postmarketing reports of cases occurring as early as weeks after infusion, with possible fatal outcomes. The incidence of these T-cell malignancies is estimated at approximately 0.1%, though overall secondary malignancies occur in about 3.6% of patients, necessitating ongoing surveillance.^[22]^[23] Other long-term risks include infections, driven by persistent B-cell aplasia and associated neutropenia, with an incidence exceeding 45% in non-Hodgkin lymphoma patients treated with axicabtagene ciloleucel, including grade 3 or higher events in 17%. Hypogammaglobulinemia develops in 46% to 62% of patients at 12 months post-infusion due to prolonged B-cell depletion, often requiring intravenous immunoglobulin (IVIG) replacement therapy at doses of 0.4 to 0.5 g/kg every 4 to 8 weeks if immunoglobulin G levels fall below 400 mg/dL or recurrent infections occur. Cytopenias, particularly grade 3 or 4 anemia and thrombocytopenia, affect 30% to 40% of patients in the early post-infusion period, with late-onset rates of 2% to 22% for neutropenia, thrombocytopenia, and anemia, managed through supportive care such as cytokine administration or stem cell boosts if persistent.^[24]^[23] Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), also termed immune effector cell-associated HLH-like syndrome (IEC-HS), is a rare hyperinflammatory complication following axicabtagene ciloleucel infusion, characterized by sustained CAR T-cell and macrophage activation leading to excessive cytokine release (e.g., IFN-γ), cytopenias, hyperferritinemia, coagulopathy, and organ damage, often emerging after initial cytokine release syndrome resolution. Pathophysiologically, it involves dysregulated immune effector cell activity mimicking classic HLH but distinct in its CAR T-specific context. Management entails prompt initiation of corticosteroids (e.g., dexamethasone 10 to 40 mg daily) as first-line therapy, with interleukin-1 receptor antagonists like anakinra (100 to 200 mg every 6 to 12 hours) for refractory cases; second-line options include Janus kinase inhibitors such as ruxolitinib (10 mg twice daily) or etoposide (50 to 100 mg/m² single dose) for life-threatening progression, alongside supportive measures for cytopenias and infections.^[24]^[25] Long-term monitoring for patients treated with axicabtagene ciloleucel includes lifelong annual follow-up for secondary malignancies, with immediate reporting of any new cancers to regulatory authorities; FDA-mandated safety follow-up studies extend up to 15 years from approval, following the removal of REMS requirements in June 2025. Infection prophylaxis is recommended, such as acyclovir for herpesvirus reactivation and trimethoprim-sulfamethoxazole for Pneumocystis jirovecii, alongside regular immunoglobulin level assessments and blood count monitoring to mitigate risks of recurrent infections and cytopenias.^[22]^[24]^[23]^[26]

Clinical development

Pivotal clinical trials

The ZUMA-1 trial was a multicenter, single-arm, pivotal phase 2 study evaluating axicabtagene ciloleucel in 101 patients with relapsed or refractory large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD19 antibody therapy.^[7] Patients received a single infusion of axicabtagene ciloleucel at a target dose of 2 × 10^6 CAR T cells per kg following lymphodepleting chemotherapy.^[7] The primary endpoint was the objective response rate, which was 82%, with a complete response rate of 54%; at a median follow-up of 15.1 months, the median duration of response among responders was not reached.^[7] Longer-term analysis at 2 years showed a median overall survival of 25.8 months, with durable responses in a subset of patients.^[27] Serious adverse events, including cytokine release syndrome in 94% of patients (13% grade 3 or higher) and neurologic events in 64% (28% grade 3 or higher), highlighted the need for risk evaluation and mitigation strategies, contributing to the establishment of a Risk Evaluation and Mitigation Strategy (REMS) program for axicabtagene ciloleucel.^[7] The ZUMA-7 trial was a randomized, open-label, phase 3 study comparing axicabtagene ciloleucel with standard-of-care second-line therapy (chemotherapy followed by high-dose therapy and autologous stem cell transplantation in responders) in 359 patients with large B-cell lymphoma refractory to or relapsed within 12 months after first-line immunochemotherapy.^[14] Eligible patients were randomized 1:1 to receive either axicabtagene ciloleucel after lymphodepletion or standard therapy; the primary endpoint was event-free survival.^[14] At a median follow-up of 24.9 months, the event-free survival hazard ratio favored axicabtagene ciloleucel (0.398; 95% CI, 0.320 to 0.498), with 24-month event-free survival rates of 40.8% versus 15.8%.^[14] The objective response rate was 83% in the axicabtagene ciloleucel arm (versus 61% with standard therapy), and updated analyses confirmed an overall survival benefit, with a 3-year overall survival rate of 63.6% versus 45.5%.^[28] Grade 3 or higher adverse events occurred in 85% of axicabtagene ciloleucel-treated patients, primarily cytokine release syndrome (7%) and neurologic events (22%).^[14] The ZUMA-5 trial was a single-arm, phase 2 study assessing axicabtagene ciloleucel in 146 patients with relapsed or refractory indolent non-Hodgkin lymphoma, including 117 with follicular lymphoma and 29 with marginal zone lymphoma, who had received at least two prior lines of therapy.^[29] Patients underwent lymphodepleting chemotherapy followed by a single axicabtagene ciloleucel infusion.^[29] The primary endpoint of objective response rate was 91%, with a complete response rate of 74%; the median duration of response was 38.6 months at a median follow-up of approximately 40 months.^[30] Cytokine release syndrome occurred in 78% of patients (6% grade 3), and neurologic events in 53% (12% grade 3).^[29] Updated 5-year follow-up data from ZUMA-5, reported in 2025, confirmed sustained efficacy in 159 enrolled patients with relapsed or refractory indolent non-Hodgkin lymphoma, showing an objective response rate of 90%, a median duration of response of 60.4 months, and a median progression-free survival of 62.2 months.^[31] In the ZUMA-12 trial, a phase 2 single-arm study of axicabtagene ciloleucel as first-line consolidative therapy in 35 efficacy-evaluable patients with high-risk large B-cell lymphoma (double-hit or double-expressor subtypes) after frontline chemoimmunotherapy, 3-year follow-up demonstrated a complete response rate of 86% and a progression-free survival rate of 75%.^[32] These pivotal trials, including ZUMA-1, ZUMA-7, ZUMA-5, and ZUMA-12, primarily featured single-arm designs for phase 2 studies, limiting direct comparisons to control groups in those contexts, and generally excluded patients with active central nervous system involvement to mitigate risks of neurologic toxicity.^[7]^[14]^[29]^[32]

Regulatory approvals

Axicabtagene ciloleucel received its initial approval from the U.S. Food and Drug Administration (FDA) on October 18, 2017, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, after two or more lines of systemic therapy.^[2] This approval was supported by breakthrough therapy designation, priority review, and orphan drug status for relevant indications such as DLBCL (granted March 2014), primary mediastinal B-cell lymphoma (April 2016), and follicular lymphoma (April 2016).^[1] The initial label included boxed warnings for cytokine release syndrome and neurologic toxicities.^[1] Subsequent FDA label expansions broadened access. On March 5, 2021, approval was extended to adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy, based on data from the ZUMA-5 trial. On April 1, 2022, the indication was further expanded to include adult patients with LBCL that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy, supported by the ZUMA-7 trial.^[4] In April 2024, the FDA updated the boxed warnings to include the risk of secondary malignancies, particularly T-cell malignancies, following reports from clinical trials and post-marketing surveillance.^[22] Additionally, in 2024, the FDA granted regenerative medicine advanced therapy (RMAT) designation for its evaluation in first-line therapy for high-risk LBCL.^[33] In the European Union, the European Medicines Agency (EMA) granted marketing authorization for axicabtagene ciloleucel on August 23, 2018, for adult patients with relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma after two or more lines of systemic therapy.^[34] Expansions occurred in 2022, including approval on April 22 for second-line treatment of DLBCL and high-grade B-cell lymphoma refractory to or relapsing within 12 months of first-line chemoimmunotherapy, and on June 21 for relapsed or refractory follicular lymphoma after three or more lines of systemic therapy.^[35]^[36] Health Canada authorized axicabtagene ciloleucel on February 13, 2019, for adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy.^[37] In the United Kingdom, the National Institute for Health and Care Excellence (NICE) recommended it in February 2023 for second-line treatment of DLBCL or high-grade B-cell lymphoma refractory to or relapsing within 12 months of first-line chemoimmunotherapy.^[38] As part of post-marketing commitments, the FDA requires ongoing long-term safety studies, including a prospective, multi-center observational study to assess the risk of secondary malignancies following axicabtagene ciloleucel treatment; these remain active as of 2025.^[1]

Society and culture

Commercial names

Axicabtagene ciloleucel is marketed under the primary brand name Yescarta, developed and commercialized by Kite Pharma, Inc., a wholly owned subsidiary of Gilead Sciences, Inc.^[39] The established generic name for the therapy is axicabtagene ciloleucel, designated as the International Nonproprietary Name (INN) by the World Health Organization to standardize nomenclature for this chimeric antigen receptor (CAR) T-cell product.^[40]^[9] Internationally, Yescarta is the consistent brand name across major markets including the United States, European Union, and Canada, reflecting uniform marketing following regulatory approvals in these regions; as an autologous cell-based biologic therapy, it is strictly prescription-only with no over-the-counter availability.^[39] In the United States, Yescarta received orphan drug designation for the treatment of diffuse large B-cell lymphoma, granting seven years of market exclusivity for the initial indication approved on October 18, 2017, which expired on October 18, 2024; a subsequent approval on April 1, 2022, for second-line treatment extended exclusivity for that indication until April 1, 2029, with no pediatric exclusivity granted as safety and efficacy in pediatric patients remain unestablished.^[41]^[1]

Manufacturing and supply

Axicabtagene ciloleucel is produced through an autologous manufacturing process that begins with leukapheresis to collect the patient's peripheral blood mononuclear cells, which are then transported to a centralized Kite Pharma facility for processing. At the facility, T cells are enriched and activated using anti-CD3 antibody and interleukin-2, followed by transduction with a replication-incompetent retroviral vector encoding the anti-CD19 chimeric antigen receptor (CAR) transgene. The transduced T cells are subsequently expanded in bioreactors over approximately 7-10 days, washed, formulated into a suspension, and cryopreserved in a solution containing 5% dimethyl sulfoxide (DMSO) and 2.5% human serum albumin.^[42] Manufacturing occurs at Kite's commercial facilities, including sites in El Segundo and Oceanside, California, and Frederick, Maryland, in the United States, as well as a dedicated facility in Amsterdam, Netherlands, for European supply, which became operational in 2020 to address growing demand. The process adheres to current good manufacturing practice (cGMP) standards, with rigorous quality control measures including sterility testing, patient identity verification at multiple steps, and potency assays ensuring the final product meets the target dose of 2 × 10^6 CAR-positive viable T cells per kg body weight (up to a maximum of 2 × 10^8 cells). Release criteria emphasize high transduction efficiency and cell viability, typically requiring greater than 15% viable CAR-positive cells to confirm product potency.^[43]^[44]^[42] Real-world manufacturing yields a success rate of approximately 97% since approval in 2017, though failure rates range from 3-4% overall, primarily due to insufficient T-cell viability or low transduction efficiency in patient-derived cells; second attempts can be initiated if needed, with success rates exceeding 95% in second-line settings. The vein-to-vein time, from leukapheresis to infusion, averages 24-27 days in clinical trials but extends to a median of 30.6 days in real-world use, influenced by shipping and processing logistics; recent process optimizations approved by the FDA in 2024 have reduced manufacturing turnaround from 16 to 14 days, enhancing predictability.^[45]^[46]^[47] Supply challenges have included capacity limitations, particularly during 2020-2021 when COVID-19 disruptions led to leukapheresis delays, facility staffing issues, and extended waitlists at authorized treatment centers (ATCs), prompting expansions like the Amsterdam site and a 50% capacity increase via the Frederick facility. To mitigate ongoing bottlenecks, Kite has invested in additional infrastructure and process improvements, reducing global wait times and enabling broader access. In October 2025, Kite established a logistics facility in Japan to manage storage and distribution, improving access in the Asian market.^[48]^[43]^[49]^[50]

References

[1]
[PDF] YESCARTA - Package Insert and Medication Guide - FDA
YESCARTA is stable at room temperature for up to 3 hours after thaw. Gently agitate the product bag during YESCARTA infusion to prevent cell clumping. After ...
[2]
FDA approves axicabtagene ciloleucel for large B-cell lymphoma
Oct 25, 2017 · On October 18, 2017, the Food and Drug Administration granted regular approval to axicabtagene ciloleucel (YESCARTA, Kite Pharma, Inc.)
[3]
FDA grants accelerated approval to Yescarta for follicular lymphoma
Mar 8, 2021 · The new prescribing information for Yescarta will be posted here when available. This indication is approved under accelerated approval ...<|control11|><|separator|>
[4]
FDA approves axicabtagene ciloleucel for second-line treatment of ...
Apr 1, 2022 · The Food and Drug Administration approved axicabtagene ciloleucel (Yescarta, Kite Pharma, Inc.) for adult patients with large B-cell lymphoma (LBCL)
[5]
[PDF] October 18, 2017 Approval Letter - YESCARTA - FDA
Oct 18, 2017 · Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. The review of this product ...
[6]
Managing leukapheresis in adult and pediatric patients eligible for ...
Regarding the procedure for patients with a low PLT count, it is advisable to postpone, if possible, leukapheresis by at least one week in order to optimize ...
[7]
Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B ...
Dec 10, 2017 · A phase 1 multicenter study (ZUMA-1) involving seven patients with refractory large B-cell lymphoma showed that axi-cel could be centrally ...
[8]
Five-year follow-up of ZUMA-1 supports the curative potential of ...
May 11, 2023 · Axicabtagene ciloleucel induced long-term survival with no new safety signals in patients with refractory LBCL.
[9]
[PDF] Yescarta, INN-axicabtagene ciloleucel - European Medicines Agency
After Yescarta infusion, pharmacodynamic responses were evaluated by measuring transient elevation of cytokines, chemokines, and other molecules in blood over a ...
[10]
Tumor burden, inflammation, and product attributes determine ...
Oct 9, 2020 · Axi-cel durable responses were associated with low baseline tumor burden, low systemic inflammation, and high product CCR7+CD45RA+ T cells.
[11]
Clinical Pharmacology and Determinants of Response to UCART19 ...
Several factors, including lymphodepleting chemotherapy (19, 20), tumor burden (21, 22), targeted antigen expression level (23), CAR design, and CAR-T cell ...
[12]
Chimeric antigen receptor T‐cell therapies: Optimising the dose
Mar 1, 2020 · 83 Patient factors, such as age, underlying disease and the number of circulating T-lymphocytes influence the probability of successful CAR T- ...
[13]
Cytokine release syndrome and associated neurotoxicity in cancer ...
May 17, 2021 · The pathophysiology of CRS can be divided into five main phases. Phase 1 involves the trafficking of CAR T cells to the tumour site following ...
[14]
Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell ...
Dec 11, 2021 · Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade ...
[15]
ASTCT Consensus Grading for Cytokine Release Syndrome and ...
The CARTOX CRS grading differs slightly from the Lee criteria by including grade 1 organ toxicity to be considered under grade 1 CRS and defining fever ...
[16]
Comparing CAR T-cell toxicity grading systems: application of the ...
Feb 21, 2020 · According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas ...Abstract · Introduction · Results · Discussion
[17]
Assessment and Management of Cytokine Release Syndrome and ...
This review will discuss CRS and neurotoxicity associated with CD19 CAR-T cell therapies, including clinical presentation, risk factors, pathophysiology and ...
[18]
Clinical and radiologic correlates of neurotoxicity after axicabtagene ...
Aug 21, 2020 · Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen ...
[19]
ASTCT Consensus Grading for Cytokine Release Syndrome and ...
Dec 25, 2018 · The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies.
[20]
Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in ...
Prophylactic tocilizumab is not recommended to prevent CAR T-cell–related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain.
[21]
FDA Requires Boxed Warning for T cell Malignancies
Apr 18, 2024 · FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous Chimeric Antigen ...
[22]
Late complications and long-term care of adult CAR T-cell patients
Dec 6, 2024 · These late complications, defined as occurring more than 90 days after CAR T-cell infusion, include cytopenias, infections, secondary malignancies, and delayed ...
[23]
None
### Summary of Yescarta Prescribing Information: Warnings and Precautions
[24]
https://www.yescartahcp.com/content/dam/gp-hcp-yescarta-hcp/pdf/prescribing-information.pdf
[25]
Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma
Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 2023;141:2307-2315 ...
[26]
Three-year follow-up analysis of first-line axicabtagene ciloleucel for ...
May 15, 2025 · First-line axi-cel demonstrated an 86% complete response rate and 3-year PFS rate of 75% in efficacy-evaluable patients with high-risk LBCL.
[27]
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30864-7/fulltext
[28]
Yescarta | European Medicines Agency (EMA)
Other information about Yescarta. Yescarta received a marketing authorisation valid throughout the EU on 23 August 2018.Overview · Product information · Authorisation details · Assessment history
[29]
[PDF] Assessment report - Yescarta - European Medicines Agency
Apr 22, 2022 · The pharmacokinetic and pharmacodynamic data for axicabtagene ciloleucel in this application are based on 1 clinical study: KTE-C19-105 (ZUMA-5) ...
[30]
[PDF] Orphan Maintenance Assessment Report - Yescarta II-0042 - EMA
Jun 21, 2022 · The approved therapeutic indication “Treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after 3 or more ...<|separator|>
[31]
Summary Basis of Decision for Yescarta
On February 13, 2019, Health Canada issued a Notice of Compliance to Gilead Sciences Canada, Inc. for the drug product Yescarta. The market authorization was ...
[32]
Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma ...
Feb 28, 2023 · This guidance updates and replaces NICE technology appraisal guidance 559 on axicabtagene ciloleucel for treating diffuse large B-cell lymphoma ...Missing: date | Show results with:date
[33]
YESCARTA | FDA
Oct 28, 2025 · Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. For the treatment of adult ...
[34]
[PDF] Executive Summary - World Health Organization (WHO)
Dec 4, 2020 · Axicabtagene ciloleucel (marketed by Kite Pharma under the tradename Yescarta®) is a CD19- directed, genetically modified, autologous T-cell ...
[35]
Search Orphan Drug Designations and Approvals - FDA
Approved Labeled Indication: Treatment of adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within ...
[36]
Geoffrey Biegler - Partner - Bio // Cooley // Global Law Firm
Trial counsel for Kite in litigation over its chimeric antigen receptor T-cell (CAR-T) cancer product Yescarta, including putting on Kite's written description ...
[37]
Introducing biosimilar competition for cell and gene therapy products
Jul 15, 2024 · Yescarta was covered by the '190 Patent claim because it contained an scFv capable of binding to a particular target, CD19, found on certain ...
[38]
[PDF] yescarta-pi.pdf
What are the ingredients in YESCARTA? Active ingredients: axicabtagene ciloleucel. Inactive ingredients: albumin (human); DMSO. YESCARTA is a trademark of Kite ...
[39]
Kite Receives European Medicines Agency Approval for CAR T Cell ...
Jun 12, 2020 · Kite's European manufacturing facility, designed and dedicated to the manufacture of individualized cell therapies, is now fully operational.
[40]
Kite Announces Plans for New State-of-the-Art Facility to Expand ...
The Frederick County facility will become part of Kite's growing commercial manufacturing network that includes sites in California and the Netherlands .
[41]
YESCARTA® (axicabtagene ciloleucel) Clinical Trial Results
The FDA has approved YESCARTA for multiple uses based on the outcomes of these trials. For LBCL patients whose cancer returned after their first treatment ...
[42]
New Kite Clinical Research and Real-World Evidence for Yescarta ...
Jun 14, 2024 · Real-World Manufacturing Experience of Axicabtagene Ciloleucel for Patients with Relapsed or Refractory Large B-Cell Lymphoma Treated in ...
[43]
Kite Receives U.S. FDA Approval of Manufacturing Process Change ...
Jan 30, 2024 · New Median Turnaround Time from Leukapheresis to Product Release in U.S. Anticipated to be Reduced from 16 Days to 14 Days –.
[44]
The race to deliver CAR-T cancer therapy during the pandemic | STAT
Nov 30, 2020 · In 2021, Kite expects results from one clinical trial, for instance, that if successful, could expand Yescarta to a new population of lymphoma ...
[45]
Gilead's Kite receives US FDA ok for Maryland CAR-T plant
The 20-acre site in Frederick, Maryland will produce CAR-T therapy Yescarta and increase its network capacity by 50%, says Kite.