“Electric power boost” for CAR-T-cell potency

Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized cancer treatment. However, its long-term efficacy and broader application are limited because of its antigen insensitivity, poor persistence, and T-cell exhaustion. A recent study published by Xu et al. revealed a novel CAR engineering strategy that overcomes these difficulties by incorporating a modified CD3ε intracellular domain, E_B6I, into the conventional CAR structure [1]. This modification enhances antigen sensitivity and sustains the cytotoxic activity of CAR-T cells, demonstrating promising efficacy in treating various tumor models, including solid tumors and hematological malignancies. This strategy could be applied to different CAR types, including 28Z and BBZ CARs, underscoring its transformative potential in overcoming current limitations and broadening the therapeutic scope of CAR-T-cell immunotherapy.

CARs are engineered synthetic receptors that integrate the extracellular antigen-binding domain of antibodies with intracellular signaling domains derived from the T-cell receptor (TCR) and costimulatory receptors. By employing genetic engineering to express CARs in T cells, these engineered CAR-T cells can target and eliminate tumor cells that express specific tumor-associated antigens in an MHC-independent manner [2]. This modular design reprograms T-cell specificity and function, establishing the molecular basis for CAR-T-cell immunotherapy. CAR-T-cell therapy has shown considerable success in treating relapsed or refractory B-cell malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. CD19-targeted CAR-T-cell therapies, including FDA-approved products such as kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), are commonly used in clinical settings for hematologic malignancies [3]. Recent preclinical and clinical studies have revealed the great potential of CAR-T-cell therapy for treating B-cell- and autoantibody-mediated autoimmune diseases, including lupus, necrotizing myopathy, and diffuse cutaneous systemic sclerosis [4, 5]. However, CAR-T-cell therapy encounters significant challenges in treating solid tumors, primarily due to tumor antigen heterogeneity and the exhaustion of CAR-T cells within the immunosuppressive tumor microenvironment (TME). Unlike native TCRs, conventional CARs exhibit poor antigen sensitivity and suboptimal coordination of intracellular signaling molecules. This limitation is largely due to their inability to form mature immune synapses (ISs) that integrate multiple signaling pathways. Consequently, CAR-T cells often fail to target tumor cells with low antigen expression and are susceptible to functional exhaustion, compromising their long-term efficacy [6]. Thus, optimizing the signal transduction capabilities of CARs is critical for overcoming the current clinical limitations of CAR-T-cell therapy [7].