Next generation CAR-T cells push the boundaries of lymphoma treatment

CAR-T cells, which are genetically programmed to specifically recognize and kill target cells, have altered the therapeutic landscape of lymphoma. After the tumor antigens are identified by scFv, CAR-T cells execute anti-tumor activity through granzyme and perforin secretion, inducing cell apoptosis in a Fas-FasL-dependent pathway and producing inflammatory cytokines to antagonize the immunosuppressive tumor microenvironments (TME) and induce host immune responses.

However, CAR-T cell therapy still faces many challenges owing to the heterogeneity of tumor cells, interference from TME, T cell exhaustion, as well as severe adverse events. Recent years, advances in tumor immunology and genetic engineering have driven CAR evolution. These new generations of CARs armed with diverse molecular weapons have made significant progress in enhancing the accuracy of recognition, stimulating endogenous immune responses, strengthening killing activity, resisting TME and exhaustion, and improving safety and flexibility, thus gradually overcoming the limitations of CAR-T cell therapy. This review focuses on the advancements of CAR-T cells in the treatment of lymphoma, summarizes the newly emerged modification strategies of CAR, and elucidates their potential prospects.

A team of researchers from the Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, published a review (DOI: 10.20892/j.issn.2095-3941.2024.0538) in Cancer Biology & Medicine. This paper analyzes the mechanisms of various CAR-T modification strategies in counteracting tumor immune escape and TME, while detailing the structures and functions of novel CAR-T designs. Multi-target CAR-T combats antigen loss, TRUCKs enhance cytotoxic activity and stimulate host immune responses through cytokine delivery, and immune checkpoint-switching receptor converts inhibitory signals into immune-activating stimuli to overcome TME-induced exhaustion. Beyond clinically established CAR-T therapies, the review also emphasizes the roles of universal CAR-T (including iPSC-derived, autologous, and in vivo-generated CAR-T), epigenetics, and metabolism. Notably, glycolysis, oxidative phosphorylation, histone acetylation, and DNA methylation interact in a tightly regulated network to influence CAR-T cell phenotype and exhaustion, ultimately shaping systemic antitumor immunity.

Collectively, superior CAR-T cells are expected to have accurate identification, strong killing ability, stability and persistence, high security and flexibility, and easier accessibility. More sophisticated modifications mean greater operational difficulties and higher genetic risks. There may be contradictions among a variety of strategies, and we need to find a balance between the efficacy and memory, lethality and safety.

This work was supported by grants from the Science Technology Department of Zhejiang Province (Grant No. 2021C03117), Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2023ZD0501300), National Natural Science Foundation of China (Grant No. 82170219), and Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ24H080009).