Dual-target CAR-T cell therapy: A new strategy to improve the therapeutic effect of hematological malignancies

Chimeric antigen receptor T cell (CAR-T) therapy represents a significant milestone in tumor immunotherapy, demonstrating transformative efficacy in the treatment of hematological malignancies through the genetic modification of patients' T cells to specifically target tumor antigens. In 2017, the FDA approved second-generation CAR-T cell therapies targeting CD19, such as Kymriah and Yescarta, for the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL) and diffuse large B-cell lymphoma (DLBCL). The advent of CAR-T cell therapy in hematological malignancies has not only redefined therapeutic approaches but also catalyzed a surge in global research related to CAR-T cells (Huang et al., 2024, Miao et al., 2022b). To date, CAR structures have evolved from the first to the fifth generation (Fig. 1). The dynamic advancement of CAR-T cell technology offers renewed hope and potential for future cancer treatments.

Nevertheless, the clinical application of single-target CAR-T still faces some challenges. First of all, antigen escape represents a significant challenge in the clinical implementation of single-target CAR-T cell therapy. This phenomenon can result in therapeutic failure and restrict the overall efficacy of the treatment. These mechanisms include antigen gene mutation, defects in antigen processing, antigen redistribution, lineage transformation, epitope masking, and phagocytosis-mediated antigen loss (Lin et al., 2024). Secondly, on-target off-tumor toxicity poses a constraint on balancing the efficacy and safety of CAR-T cell therapy. Moreover, the antigenic heterogeneity of malignant tumors, manifested as spatial and temporal heterogeneity, represents one of the core mechanisms underlying the drug resistance of CAR-T cell therapy (Ai et al., 2023, Guzman et al., 2023). For hematological malignancies, the success of CAR-T cell therapy is also constrained by tumor antigen heterogeneity, resulting in drug resistance and recurrence (Zhang et al., 2023).

In recent years, the field of dual-target CAR-T cell therapy has developed rapidly and become an important research direction in cancer immunotherapy. This approach enables the recognition of two distinct tumor antigens, thereby broadening the recognition spectrum of CAR-T cells, enhancing their anti-tumor efficacy, and minimizing off-target effects. This therapeutic approach has demonstrated considerable benefits in the management of hematological malignancies, particularly in addressing antigen loss and recurrence (Imai et al., 2024). For instance, CD19/CD37 dual-target CAR-T cells have exhibited notable antitumor activity in B cell tumor models characterized by antigen loss (Imai et al., 2024). Furthermore, dual-target CAR-T cell therapy directed at CD19 and CD22 has been associated with higher complete response rates in patients with acute lymphoblastic leukemia (ALL) and has shown enhanced efficacy in high-risk patient populations, as evidenced by clinical outcomes (Liu et al., 2023).

While CAR-T cell therapy has achieved significant advancements in the treatment of hematological malignancies, a comprehensive review of dual-target CAR-T cell therapy remains lacking. This review will provide a comprehensive and in-depth analysis of the unique advantages, research progress, challenges, and coping strategies of dual-target CAR-T cell therapy in treating hematological malignancies. It aims to offer a valuable reference for research and clinical applications in this field and to promote the further development of dual-target CAR-T cell therapy.

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