T-Cell–Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma - Current Evidence, Sequencing, and Future Directions

Sep 30, 2026

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Relapsed/refractory mantle cell lymphoma remains a therapeutic challenge, especially for high-risk patients and those previously exposed to Bruton's tyrosine kinase inhibitors. T-cell–redirecting immunotherapies, including CAR-T therapy and bispecific antibodies, have reshaped treatment strategies. CAR-T approaches such as brexu-cel and liso-cel provide high response rates and durable remissions, but require bridging care, face logistical constraints, and can cause severe toxicities like CRS and ICANS. Bispecific antibodies targeting CD20 and CD3 offer off-the-shelf repeat dosing with generally manageable toxicity. The review details CRS mitigation with step-up dosing, corticosteroids, and anti-IL6 therapy, highlights hematologic risks and infection monitoring, and outlines evidence supporting rational sequencing and combination regimens, including use as bridge to CAR-T or consolidation after BisAb response, to improve long-term outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Disease background and biology

Prognostic stratification and high-risk features

Therapeutic landscape of T-cell–redirecting immunotherapies

CAR-T therapy overview

Bispecific antibodies overview

Toxicity mitigation and monitoring

Sequencing strategies and future directions

European Journal of Haematology REVIEW OPEN ACCESS T-Cell–Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma: Current Evidence, Sequencing, and Future Directions Santino Caserta1 | Enrica Antonia Martino1 | Ernesto Vigna1 | Antonella Bruzzese1 | Nicola Amodio2 | Eugenio Lucia1 | Virginia Olivito1 | Caterina Labanca1 | Francesco Mendicino1 | Fortunato Morabito3 | Massimo Gentile1,4 1Department of Onco-Haematology, Haematology Unit, Cosenza, Italy | 2Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy | 3AIL Sezione di Cosenza, Cosenza, Italy | 4Department of Pharmacy, Health and Nutritional Science, University of Calabria, Rende, Italy Correspondence: Massimo Gentile ([massimo.gentile@unical.it](massimo.gentile@unical.it)) Received: 13 September 2025 | Revised: 16 October 2025 | Accepted: 18 October 2025 Funding: This work was supported by the PNRR (PNRR-MAD-2022-12375673) . Keywords: bispecific antibodies | CAR-T therapy | immunotherapy | mantle cell lymphoma | treatment sequencing ABSTRACT 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 ofT-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. 1 | Introduction Mantle cell lymphoma (MCL) is a rare and biologically heterogeneous subtype of non-Hodgkin lymphoma (NHL) . Its clinical spectrum ranges from indolent forms associated with long-term survival to highly aggressive variants with dismal outcomes. At diagnosis, the majority of patients present with advanced-stage disease and frequent extranodal involvement, including bone marrow (53%–82%), peripheral blood (≈50%), liver (≈25%), and gastrointestinal tract (20%–60%) . The molecular hallmark of This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd. European Journal of Haematology, 2026; 116:129–141 129 [https://doi.org/10.1111/ejh.70063](https://doi.org/10.1111/ejh.70063) MCL is the CCND1 translocation, result

FAQs

Why is relapsed/refractory mantle cell lymphoma difficult to treat?

It is challenging particularly in patients with high-risk features or prior exposure to Bruton's tyrosine kinase inhibitors. Disease biology and prognosis vary widely, contributing to inconsistent outcomes.

What benefits and limitations are associated with CAR-T therapy in this setting?

CAR-T therapies such as brexu-cel and liso-cel can induce high overall response rates and durable remissions, even after heavy pretreatment. Limitations include logistical constraints, need for bridging therapy, and risks of severe toxicities like CRS and ICANS.

How do bispecific antibodies fit into treatment and what toxicities require attention?

Bispecific antibodies targeting CD20 and CD3 provide off-the-shelf, repeatable immunotherapy, often suitable for outpatient use, with generally manageable toxicities. CRS mitigation may involve step-up dosing, corticosteroids, and anti-IL6 therapy, while hematologic toxicity and infections require vigilant monitoring.

Sep 30, 2026

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