Cancer Genetics and Epigenetics, 2025, Vol.13, No.3, 136-144 http://medscipublisher.com/index.php/cge 140 4.3 Toxicity and safety optimization management strategies Effective control of the side effects brought by CAR-T treatment is very important for improving the therapeutic effect of patients. When the symptoms are mild, supportive treatment is mainly adopted; For more severe CRS and ICANS, tocilizumab (an IL-6 receptor blocking drug) and targeted drugs such as corticosteroids will be used (Xiang et al., 2020; Gomez et al., 2021; Chohan et al., 2023). Early detection and timely treatment of side effects can prevent the occurrence of life-threatening serious complications (Gomez et al., 2021; Chohan et al., 2023). To enhance the safety of treatment, it is also necessary for multidisciplinary medical teams to collaborate, adopt standardized monitoring procedures, and popularize relevant knowledge among patients. Only in this way can adverse reactions be responded to quickly (Gomez et al., 2021). Currently, researchers are developing CAR-T cell designs with limited toxicity and non-viral gene editing technologies to further reduce the risk of severe side effects while ensuring therapeutic effects (Zhang et al., 2022; Chohan et al., 2023; Zheng et al., 2025). 5 Challenges and Limitations of CAR-T Therapy 5.1 Poor persistence and recurrence causes: antigen evasion and T-cell function decline One major problem faced by CAR-T cell therapy is that the therapeutic effect is difficult to be maintained for a long time. Many patients will experience recurrence after the initial remission of the disease. There are two main reasons for this situation: One is antigen evasion, that is, tumor cells no longer express or change the target antigen (such as CD19 or BCMA), making CAR-T cells unable to recognize it; The second is the decline of T cell function, which refers to the loss of cytotoxicity of CAR-T cells due to continuous stimulation or the suppression of immune function by the tumor microenvironment (Figure 2) (Sterner and Sterner, 2021; Chen et al., 2022; Gumber and Wang, 2022; Aghebati-Maleki et al., 2023; Gómez-Melero et al., 2025). These factors have weakened the long-term efficacy of CAR-T therapy, especially when treating hematological malignancies. Figure 2 Multi-targeted CAR-T cell approaches (Adopted from Gómez-Melero et al., 2025) Image caption: (A): Co-administration: a strategy involving a cocktail or sequential infusion of two single CAR-T cell products, each transduced independently with a different vector; (B): Co-transduction: a strategy generating a mixed population composed of two single CAR-T cells and one dual CAR-T cell, generated by the co-transduction with two vectors, each encoding a different CAR; (C): Bicistronic CAR: dual CAR-T cells produced by the transduction of a bicistronic vector, which introduces two separate CARs into a single cell; (D): Tandem CAR: Bispecific CAR-T cells expressing a single CAR with two antigen-binding domains, where the VL-VH sequences of one scFv are directly linked to the VL-VH sequences of the other scFv; (E) Tandem Loop CAR: a variant of the tandem CAR, in which the VL-VH sequences of one scFv are intercalated with those of the other scFv, forming a bivalent loop CAR; CAR: chimeric antigen receptor; scFv: Single-chain variable fragments; VH: Variable heavy chain; VL: Variable light chain (Adopted from Gómez-Melero et al., 2025) Researchers attempt to address the problem of antigen evasion by developing CAR-T cells capable of recognizing multiple targets, or tandem CAR-T cells, while enhancing the survival ability of CAR-T cells and avoiding premature functional decline (Gumber and Wang, 2022). However, these methods are still in the research stage. Among many patient groups, disease recurrence remains a huge obstacle to achieving long-term cure (Sterner and Sterner, 2021; Chen et al., 2022; Gómez-Melero et al., 2025). 5.2 There are significant individual differences among patients, and the treatment effect is difficult to predict There are significant differences among patients, including disease characteristics, immune status, and past treatment experiences, etc. These differences lead to different responses to CAR-T treatment (Abreu et al., 2019;
RkJQdWJsaXNoZXIy MjQ4ODYzNA==