From CAR-T to CAAR-T: redefining targeting strategies in B-cell malignancies through idiotype-directed cellular...

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of selected hematologic malignancies, particularly relapsed or refractory large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, currently approved CAR-T strategies largely rely on lineage-associated or differentiation antigens, such as CD19 or BCMA, and therefore do not selectively distinguish malignant B cells from their normal counterparts. This limitation contributes to on-target, off-tumor toxicity, including B-cell aplasia, hypogammaglobulinemia, infectious complications, and prolonged immune dysfunction. In addition, CAR-T therapy remains associated with cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, manufacturing complexity, and variable efficacy across disease entities, particularly in chronic lymphocytic leukemia. Chimeric autoantibody receptor T-cell (CAAR-T) therapy represents a conceptually distinct approach in which engineered T cells are designed to recognize disease-defining immunoglobulin structures, including surface immunoglobulin or B-cell receptor idiotypes. This strategy has been most extensively explored in autoimmune diseases, where CAAR-T cells can selectively eliminate autoreactive B-cell populations while sparing the broader B-cell compartment. Its application in B-cell malignancies remains largely hypothetical, but the biological principle is attractive because many B-cell neoplasms are defined by clonotypic immunoglobulin rearrangements. In this review, we provide a disease-specific and translationally oriented assessment of idiotype-directed CAAR-T therapy in B-cell malignancies. We summarize the current evidence supporting CAAR-T biology, critically evaluate its potential in chronic lymphocytic leukemia, indolent lymphomas, multiple myeloma, and minimal residual disease, and discuss key biological, economic, manufacturing, and regulatory barriers. At present, CAAR-T should not be viewed as a near-term replacement for approved CAR-T therapies, but rather as a hypothesis-generating precision platform requiring rigorous disease-specific validation.