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

Abstract

xicabtagene ciloleucel is an autologous, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with significantly improved efficacy in patients with refractory large B-cell lymphoma (LBCL) compared with other currently available treatment options. 1 Although standard-of-care therapies can cure approximately 60% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), 2,3 outcomes for patients with relapsed or refractory LBCL are poor. 4-8 A large, international, retrospective patient-level analysis of outcomes in refractory LBCL prior to the availability of CAR T-cell therapy, SCHOLAR-1, reported an objective response rate (ORR) of 26%, a complete response (CR) rate of 7%, and a short median overall survival of 6.3 months, 1 highlighting the need for innovative therapeutic approaches.The antigen CD19 is an optimal target for CAR T-cell therapy given its expression across a wide range of B-cell cancers and its restricted expression in healthy tissues. 9,10 However, targeting CD19 can lead to B-cell aplasia and hypogammaglobulinemia, similar to routinely used CD20-targeting monoclonal antibody therapies, and immunoglobulin supplementation can mitigate the increased risk of infections attributable to B-cell aplasia. 11 B-cell recovery has been observed 2 years after receiving anti-CD19 CAR T-cell therapy in patients with ongoing CR. 12 The cell product that became axicabtagene ciloleucel was collaboratively developed with Kite, a Gilead Company, and the National Cancer Institute (Figure 1A). [13][14][15][16][17] Early work revealed that, although first-generation CAR T cells (ie, CARs with only a single T-cell signaling domain) demonstrated cytotoxic activity, they lacked functional persistence. [18][19][20] For optimal T-cell activity, antigen recognition must occur in conjunction with appropriate costimulation, such as through CD28. 21 In 2009, Kochenderfer and colleagues 22 described the development of the CAR construct used in axicabtagene ciloleucel, which consists of an extracellular CD19-targeting, single-chain variable fragment, an intracellular CD28 costimulatory domain, and a CD3ζ signaling domain (Figure 1B). This development was quickly followed in 2010 by, to our knowledge, the first reported successful use of this CAR in a patient with B-cell lymphoma. 13 Additional studies from the National Cancer Institute using the CD19-CD28-CD3ζ CAR demonstrated the importance of conditioning 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 we...

The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

“…For most patients, a rapid rise in inflammatory factors occurs within 5-10 days after CAR T-cell transfusion. 9,64 After the peak, CAR T-cell amplification will slow down and the level of cytokines will decrease as the tumour burden subsides. However, if the tumour has not been eliminated substantially over a period of time (e.g., 1 month), the CRS might be prolonged.…”

B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

“…The two products differ in a number of respects, such as in the co-stimulatory domain engineered into its chimeric receptor: 4-1BB (CD137; to enhance memory persistence) in tisagenlecleucel and CD28 (to afford greater peak expansion) in axi-cel. In addition, tisagenlecleucel uses a lentiviral vector in the manufacturing process while axi-cel is retroviral-based [ 106 , 107 , 108 , 109 , 110 , 111 ].…”

B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

“…The two products differ in a number of respects, such as in the co-stimulatory domain engineered into its chimeric receptor: 4-1BB (CD137; to enhance memory persistence) in tisagenlecleucel and CD28 (to afford greater peak expansion) in axi-cel. In addition, tisagenlecleucel uses a lentiviral vector in the manufacturing process while axi-cel is retroviral-based [103][104][105][106][107][108].…”