Development and Use of the Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Axicabtagene Ciloleucel in Large B-Cell Lymphoma: A Review

Abstract

Importance: Axicabtagene ciloleucel, an anti-CD19-CD28-CD3ζ chimeric antigen receptor T-cell therapy, was the first US Food and Drug Administration-approved, genetically engineered T-cell therapy for adults with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. There has not been a US Food and Drug Administration-approved product for these cancers in more than 4 decades.

Observations: Unlike traditional anticancer therapies, axicabtagene ciloleucel is a patient-specific, live-cell product that has unique requirements for manufacturing, shipping, and storage, as well as for its administration and management of its adverse events. In addition, axicabtagene ciloleucel has demonstrated efficacy in patients with refractory LBCL. This review presents a timeline of the rapid clinical development of axicabtagene ciloleucel from bench to bedside, highlights how axicabtagene ciloleucel satisfies an unmet medical need for treatment of refractory LBCL, outlines the logistics of the production process and administration of axicabtagene ciloleucel, describes its mechanism of action, and summarizes the results of the pivotal study. This review also provides a survey of adverse events, with attention to the kinetics of their clinical presentation; discusses the management of adverse events; and offers suggestions for appropriate patient selection for safe administration of axicabtagene ciloleucel.

Conclusions and relevance: The integration of axicabtagene ciloleucel therapy into standard-of-care practice for relapsed/refractory LBCL is the beginning of a paradigm shift in the treatment of patients with LBCL and is likely to lead to improvements in their survival and curability. Timely referral to centers offering the therapy is necessary for optimal patient outcomes.

Figure 1.. Axicabtagene Ciloleucel Developmental Timeline and Structure

Developmental timeline (A) with structure of axicabtagene ciloleucel and antigen response (B). AACR indicates American Association of Cancer Research; CAR, chimeric antigen receptor; CRADA, cooperative research and development agreement; LTR, long terminal repeat; NCI, National Cancer Institute; scFv, single-chain variable fragment; ZUMA, long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma. ^aFirst clinical data reported by Kochenderfer et al. ^bAnalysis reported by Locke et al. ^cAnalysis reported by Locke et al. ^dFollow-up reported by Neelapu et al. ^eFollow-up reported by Locke et al.

Figure 2.. Axicabtagene Ciloleucel Prescribing Information and Delivery

A, Indication, limitations of use, and warning from the prescribing information. B, Axicabtagene ciloleucel (axi-cel) process from patient to manufacturer, and back to the patient at 1 °C to 10 °C. CRS indicates cytokine release syndrome; G1, grade 1; G2, grade 2; G3, grade 3.

Figure 3.. Efficacy Outcomes for Patients Treated With Axicabtagene Ciloleucel (Axi-Cel)

A, Median duration of response, 11.2 months (95% CI, 4.2-not reached [NR]). B, Median overall survival (OS), NR (95% CI, 12.8-NR); progression-free survival (PFS), 5.9 (95% CI, 3.3-15.0).

Figure 4.. Timeline of Adverse Events

Timeline of cytokine release syndrome (A) and neurologic events (B) after axicabtagene ciloleucel therapy in ZUMA-1, with exact day of the event shown, and a visual case study illustrating management of concurrent cytokine release syndrome and neurologic events (C). Time-to-onset is calculated as (day of infusion, ie, day 0) + 1. Five patients experienced grade 1 neurologic events that were ongoing at day 90 (1 patient each with encephalopathy, hypoesthesia, tremor, and memory impairment; 1 patient with encephalopathy and leukoencephalopathy), and all events subsequently resolved. Axi-Cel indicates axicabtagene ciloleucel; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ECG, electrocardiogram; G1, grade 1; G2, grade 2; G3, grade 3; ICU, intensive care unit; IV, intravenous; and MRI, magnetic resonance imaging.