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other aggressive large B-cell lymphomas: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and
lisocabtagene maraleucel (liso-cel) [Table 1]. These three CAR T-cell products were studied in separate
clinical trials [9-11] , which differ in construct design, manufacturing process, and side effect profiles but in
general are all capable of producing durable remissions in a significant proportion of patients.

Axi-cel (Yescarta) was the first anti-CD19 CAR T product approved by the FDA (2017) and the European
Medicines Agency (EMA) (2018) for DLBCL. Axi-cel is generated by transfecting bulk T-cells using a
retroviral vector and includes a CD28 co-stimulatory domain. ZUMA-1 was the pivotal single-arm phase 2
clinical trial of axi-cel in patients with DLBCL, primary mediastinal B-cell lymphoma (PMBCL), high grade
B-cell lymphoma (HGBCL) with double-hit cytogenetics, and transformed follicular lymphoma (tFL) .
[10]
Eligible patients had disease progression after at least two prior lines of therapy and were considered
chemotherapy-refractory, defined as progression or stable disease as best response to the most recent prior
treatment, or relapse within one year from ASCT. Bridging chemotherapy was not permitted and
lymphodepletion was performed with three days of fludarabine and cyclophosphamide. CAR T product was
successfully manufactured for 110 patients and ultimately infused in 101/111 enrolled patients. In a recently
updated analysis, the objective response rate (ORR) was 82% with a complete response (CR) in 58% of
patients. The progression free survival (PFS) was 39% and the median OS had not yet been reached at 27
months of median follow up [10,18] .

Tisa-cel (Kymriah) was the second anti-CD19 CAR T product to be FDA- and EMA-approved (2018) in
DLBCL. Tisa-cel is generated from bulk T-cells with a lentiviral vector and incorporates a 4-1BB co-
stimulatory domain. JULIET was the pivotal phase 2 clinical trial of tisa-cel in patients with
relapsed/refractory DLBCL, double-hit lymphoma, or tFL . Eligible patients had received at least two prior
[11]
[10]
lines of chemotherapy but in contrast to the ZUMA-1 trial , they were not required to be chemotherapy-
refractory, although 55% of the JULIET patients were considered refractory and 49% had relapsed after
ASCT. Bridging chemotherapy was allowed and was given to 92% of patients and lymphodepletion was
performed with 3 days of fludarabine and cyclophosphamide or 2 days of bendamustine. Of the 165 patients
enrolled in this study, 111 ultimately received CAR T-cells; in 12 instances, CAR T-cells were unable to be
manufactured. The ORR with tisa-cel was 52%, with a CR rate of 40%, 1 year PFS of 35%, and a 1 year OS of
49% for all treated patients (90% among patients with a CR).

Liso-cel (Breyanzi) is the third major anti-CD19 CAR T product for relapsed/refractory DLBCL and was
FDA-approved in 2021 . Similar to tisa-cel, liso-cel is manufactured using a lentiviral vector and a 4-1BB
[9]
costimulatory domain but instead of transducing bulk T-cells, CD4+ and CD8+ T-cells are separated and
transduced and then infused back into the patient at equal target doses . This defined composition
[19]
approach has been shown in preclinical data to improve CAR T-cell expansion and persistence and to
optimize antitumor properties, though the relative importance in clinical trials has yet to be definitively
[9]
established . TRANSCEND was the large seamless design clinical trial leading to the approval of liso-cel .
[20]
Eligible patients had relapsed/refractory large B-cell lymphomas (DLBCL, HGBCL with double- or triple-hit
cytogenetics, and PMBCL), transformed indolent lymphoma (follicular, marginal zone, CLL/SLL, or
lymphoplasmacytic), or grade 3B FL and had received a minimum of two prior therapies; prior stem cell
transplant (autologous or allogeneic) was permitted. Patients with secondary CNS lymphoma were eligible
[11]
for enrollment, in contrast to ZUMA-1 or JULIET , which excluded patients with CNS disease. Bridging
[10]
chemotherapy was allowed and was given to 59% of patients, lymphodepletion was performed with 3 days
of fludarabine and cyclophosphamide, and CAR T-cells were given at three different dose levels. Of the 344
patients who underwent leukapheresis, 269 ultimately received liso-cel and an additional 25 received a non-
conforming product (most commonly because one of the CD4 or CD8 cell components did not technically