Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell ma...Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid tumors.However,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies.Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies.In this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy.These insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.展开更多
基金supported by National Natural Science Foundation of China(Nos.82273202,82072996,82073349)National Key Research and Development Program(No.2022YFC2504200,China)+1 种基金Fundamental Research Funds for the Central Universities(No.2042024kf0021,China)Interdisciplinary Innovative Foundation of Wuhan University(No.XNJC202303,China).
文摘Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid tumors.However,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies.Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies.In this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy.These insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.
