CAR-T Cell Therapy vs. Bispecific T-Cell Engagers: A Comparative Review of Cellular vs. Molecular Immunotherapy in Hematologic Malignancies

Abstract

T-cell redirecting immunotherapies, namely chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers (BsAbs), have reshaped treatment for relapsed or refractory hematologic malignancies, including large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. Both platforms achieve MHC-independent, antigen-specific tumor cytotoxicity, yet differ in structure, kinetics, logistics, and toxicity, shaping how each is used clinically. This review compares autologous CAR T-cell products, engineered as living, self-amplifying cellular therapies, with off-the-shelf recombinant bispecific antibodies across pivotal trials in these three malignancies. CAR T-cell therapy produces deep, durable, treatment-free remissions after a single infusion but requires a multi-week manufacturing period, high upfront cost, and is associated with prolonged cytopenias and severe early cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Bispecific antibodies, in contrast, are immediately available, permit manageable step-up dosing suitable for outpatient use, and generally cause lower-grade acute toxicity, though repeated dosing until progression brings cumulative infection risk from sustained immunosuppression and yields lower complete remission rates. Shared resistance mechanisms, particularly antigen loss, splice-variant escape, and T-cell exhaustion, limit durability across both approaches. We discuss how prior bispecific exposure can compromise subsequent CAR T-cell manufacturing and outcomes, supporting sequencing frameworks that favor cellular therapy earlier when feasible, alongside antigen-switching strategies at relapse. Emerging solutions, including allogeneic off-the-shelf CAR-T platforms, in vivo mRNA delivery, dual-antigen targeting, and  logic-gated  constructs,  aim to merge cellular potency with   the   accessibility   of   molecular  engagers. Rational sequencing, biomarker-guided selection, and combination strategies will be central to optimizing outcomes and access to both treatment classes.