Adoptive T-cell transfer of high-affinity chimeric antigen receptor (CAR)- T cells targeting CD19 has shown impressive clinical success in treating certain B-cell malignancies. However, broader clinical application has been hindered by the development of potentially life-threatening side effects like cytokine release syndrome, accompanied by neurotoxicity. Additionally, consistent strong activation results in CAR-T cell exhaustion, which could limit their long-term functionality and thus contribute to tumor relapses in treated patients. While modifications of the CAR molecule structure have shown some influence on efficacy and persistence, their impact on toxicity profiles of CAR-T cells has been limited studied. Recent evidence suggests that affinity could serve as a suitable parameter to balance safety and maintain CAR-T cell efficacy. However, a comprehensive understanding of how receptor binding affinities affect the functionality and safety of anti-CD19 CAR-T cells is still lacking. Gaining insights into the affinity threshold, persistence, and short- and long-term functionality of variable CAR molecules can potentially enhance anti-CD19 CAR-T cell therapy and enable the exploitation of its full potential in adoptive cell therapy.

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