Exploring current evidence on bispecific CAR-T cell therapy for acute leukemias: a systematic review

Introduction Chimeric antigen receptor T cell (CAR-T cell) therapy is an immunotherapy for acute leukemias utilizing recombinant receptors specific to antigens involved in T-cell function to direct tumor cell recognition and elimination. However, major limitations include relapse due to antigen escape and tumor heterogeneity, as well as on-target off-tumor effects. Bispecific CAR-T cells are developed to overcome these issues. Method A literature search was conducted to identify relevant articles using three databases (PubMed, Scopus, ProQuest) between 2016 and 2025. Studies written in English and in vivo , in vitro , and clinical trial research designs were included. Articles without complete data and case reports were excluded. The systematic review followed PRISMA guidelines. Results Nine studies were included in the final synthesis. Bispecific CAR-T cell therapy was superior in tumor eradication and limiting adverse effects in both AML and ALL. CARs used in AML often targeted CD123 and CD33; development of more diverse targets, including cell signaling of tumor growth (FLT3, NKG2D, TIM3, FRβ), addressed heterogeneity. CD19 was the most common CAR in ALL, additionally targeting CD22, CD20, and BAFF-R; addressing CD19-negative relapse was quite common. Phase I clinical trials were done for CD19/CD22 bispecific CAR-T cells, proving effective with low incidence of cytokine release syndrome, neurotoxicity, or other adverse effects. Preclinical trials showed that bispecific CAR-T cells had longer in vivo persistence. Conclusion Bispecific CAR-T cell therapy is more effective in managing acute leukemias than conventional CAR-T cells. Future research should focus on developing diverse targets and advancing into clinical trials. Systematic Review Registration Open Science Framework (OSF) Registries https://osf.io/ , registration DOI: https://doi.org/10.17605 .