Background: Lymphomas are a heterogeneous group of malignancies arising from the clonal proliferation of B-cell, T-cell, and natural killer (NK) cell subsets of lymphocytes at different stages of proliferation, with prognosis varying by histologic subtype and molecular characteristics. It accounts for approximately 5% of malignancies, with an estimated overall survival of 72%. Lymphoma has a high incidence in highly developed regions, including North America, Europe, and Australia, with particularly high rates among U.S. Whites. Prognosis depends on the histologic type, clinical factors, and molecular characteristics. For instance, according to GLOBOCAN 2022, Non-Hodgkin lymphoma (NHL) accounted for an estimated 553,389 new cases and 250,679 deaths globally, while Hodgkin lymphoma (HL) had 82,469 new cases and 22,733 deaths worldwide. Chimeric Antigen Receptor T-cell (CAR-T) therapy is a drug that utilizes genetically engineered molecules, enabling patients' immune cells to recognize and destroy tumor cells. It is primarily used when lymphoma or leukemia has relapsed or is refractory to chemotherapeutic agents.

Methods: A comparative analysis was conducted across FDA-approved CAR-T therapies. Efficacy was assessed based on the percentage of patients showing partial or complete tumor regression, survival without disease progression, and overall survival rates. Safety was evaluated by reporting the frequency of severe side effects, including immune-related complications and adverse neurological events.

Therapies were also compared based on disease subtype, the type of molecular co-stimulatory domain used (CD28 vs. 4-1BB), and whether the CAR-T cells targeted a single antigen or dual antigens.

Results: In diffuse large B-cell lymphoma, axicabtagene ciloleucel (ZUMA-1 trial) resulted in a reduction in tumor size or complete disappearance in 82% of patients, with 54% showing no detectable cancer after treatment. The incidence of grade ≥3 cytokine release syndrome (CRS) was 13%. Lisocabtagene maraleucel resulted in a decrease in tumor burden in 74% of patients and showed better long-term survival, while causing severe immune-related side effects in 1% of cases with grade ≥ 3 CRS, compared to 13% with axicabtagene. Toxicity varied by costimulatory domain: CD28-based constructs (axi-cel) were associated with higher rates of CRS and immune effector cell-associated neurotoxicity syndrome than 4-1BB-based (costimulatorydomain) constructs (liso-cel, tisa-cel). Dual-target CARs (CD19/CD22) demonstrated promising results while maintaining a manageable safety profile. In mantle cell lymphoma (MCL), brexucabtagene autoleucel reduced or eliminated cancer in 93% of patients, with complete disappearance seen in 67%. In follicular lymphoma (FL), axicabtagene ciloleucel showed the highest percentage of patients with complete disappearance of cancer, at 79%, and also showed longer periods without disease progression. CAR-T treatments that target both CD19 and CD22 proteins reduced or eliminated cancer in 83.7% of patients, and 78.0% had no detectable disease after treatment, with manageable side effects.

Among patients with B-cell acute lymphoblastic leukemia who had previously received a stem cell transplant, those with a high number of cancer cells before starting CAR-T treatment had a 24-month event-free survival of 30.0%, compared to 55.4% in patients with a lower number of cancer cells. Patients who relapsed within 6 months after transplant had worse outcomes, with only 18.4% remaining event-free and 16.0% surviving at 24 months, compared to 55.5% and 74.8%, respectively, in those who relapsed later. No statistically significant differences in survival outcomes were observed based on age, cytogenetic risk, central nervous system involvement, or the dose of lymphodepleting chemotherapy.

Conclusion: CAR-T therapy offers subtype-specific advantages, with FL showing higher response rates and MCL demonstrating superior progression-free survival. While efficacy is well established, toxicity and relapse remain the key concerns. Costimulatory domains influence toxicity, and dual-target CAR-Ts may mitigate antigen escape. Future directions include third- to fifth-generation chimeric antigen receptors with enhanced persistence and reduced toxicity, along with standardization of long-term follow-up and accessibility remains vital to its sustainable implementation.

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2025
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