T-Cell-Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma: Current Evidence, Sequencing, and...

Relapsed/refractory (R/R) mantle cell lymphoma (MCL) remains a therapeutic challenge, particularly in patients with high-risk features or prior exposure to Bruton's tyrosine kinase inhibitors (BTKis). The advent of T-cell-redirecting immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs), has transformed the treatment landscape. CAR-T therapies, such as brexu-cel and liso-cel, induce high overall response rates and durable remissions, even in heavily pretreated or BTKi-refractory patients. However, CAR-T administration is limited by logistical constraints, the need for bridging therapy, and the risk of severe toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BsAbs, targeting CD20 and CD3, offer an off-the-shelf, repeatable immunotherapeutic option suitable for outpatient use, with generally manageable toxicities. Step-up dosing, corticosteroids, and anti-IL6 therapy mitigate CRS, while hematologic toxicity and infections require vigilant monitoring. Clinical data indicate that BsAbs are active in both CAR-T-naïve and post-CAR-T settings, providing disease control in patients ineligible for immediate CAR-T therapy. Emerging evidence supports rational sequencing and combinatorial strategies to optimize outcomes. BsAbs may be employed as a bridge to CAR-T, or CAR-T may be used to consolidate BsAb-induced remissions. Combination regimens, including CAR-T or BsAbs with BTK inhibitors or other targeted agents, are under investigation to enhance the depth and durability of response. In conclusion, CAR-T and BsAbs are complementary modalities in R/R MCL. Individualized therapeutic sequencing and rational combinations, tailored to disease biology and patient characteristics, represent the next frontier for improving long-term outcomes in this historically high-risk population.