CAR T Therapy Shows Sustained Efficacy in Relapsed/Refractory Lymphoma

Relapsed or refractory large B-cell lymphoma (R/R LBCL) represents a significant clinical challenge. For patients who fail to achieve remission or relapse after initial chemoimmunotherapy, second-line options typically include salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for transplant-eligible individuals. However, a substantial proportion of patients are either ineligible for ASCT or experience disease progression post-ASCT, leaving limited effective treatment avenues.¹ The median overall survival for patients with primary refractory LBCL or those relapsing within 12 months of initial therapy is historically poor, often less than six months.¹ This clinical context underscores the urgent need for novel therapeutic strategies capable of inducing durable responses in this high-risk population.

CAR T-Cell Therapy in R/R LBCL

Chimeric antigen receptor (CAR) T-cell therapy involves genetically modifying a patient's own T-cells to express a CAR that targets a specific antigen on cancer cells, most commonly CD19 in LBCL. These modified T-cells are then expanded ex vivo and reinfused into the patient, where they can recognize and eliminate CD19-expressing lymphoma cells.² The development of CAR T-cell therapies, including axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), has transformed the treatment landscape for R/R LBCL.³

Pivotal trials evaluating these CD19-directed CAR T-cell therapies have consistently demonstrated superior efficacy compared to historical controls and, in some cases, against standard of care. The ZUMA-1 trial, which evaluated axi-cel in adult patients with R/R LBCL after two or more lines of systemic therapy, reported an objective response rate (ORR) of 83% and a complete response (CR) rate of 58%.⁴ At a median follow-up of 51.1 months, the median overall survival was 25.8 months.⁴ The JULIET trial, investigating tisa-cel in a similar patient population, showed an ORR of 52% and a CR rate of 40%, with a 3-year overall survival rate of 33%.⁵ The TRANSCEND NHL 001 trial, examining liso-cel, reported an ORR of 73% and a CR rate of 54% in R/R LBCL patients, with a median duration of response of 10.5 months.⁶ These data highlight the capacity of CAR T-cell therapy to induce deep and durable remissions in a significant proportion of patients who previously had limited options.

Adverse events associated with CAR T-cell therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).⁷ While these toxicities can be severe, they are generally manageable with established protocols, including corticosteroids and tocilizumab.⁷ The incidence and severity of CRS and ICANS vary between different CAR T-cell products, with axi-cel generally associated with higher rates of severe CRS and ICANS compared to tisa-cel and liso-cel.⁸ Long-term follow-up data from these trials continue to demonstrate sustained responses, suggesting that a proportion of patients achieve long-term disease control or potential cure.^4-6

Further studies, such as the ZUMA-7 and TRANSFORM trials, have investigated CAR T-cell therapy in the second-line setting for patients with primary refractory LBCL or early relapse (within 12 months of first-line therapy). ZUMA-7 compared axi-cel to standard of care (salvage chemotherapy followed by ASCT) and demonstrated a significantly longer event-free survival (EFS) with axi-cel (median 8.3 months vs. 2.0 months; HR 0.40; p < 0.001).⁹ Similarly, the TRANSFORM trial showed superior EFS with liso-cel compared to standard of care (median 10.1 months vs. 2.3 months; HR 0.34; p < 0.0001).¹⁰ These results indicate a potential shift towards earlier integration of CAR T-cell therapy in the treatment algorithm for high-risk R/R LBCL patients.

Despite the promising efficacy, challenges remain, including patient eligibility, access to treatment centers, manufacturing time, and managing toxicities. Ongoing research focuses on optimizing CAR T-cell constructs, developing allogeneic CAR T-cell therapies, and identifying biomarkers to predict response and toxicity.¹¹ The EHA 2026 meeting is expected to feature updated long-term follow-up data and real-world evidence, further solidifying the role of CAR T-cell therapy in lymphoma management.