Vitamin C2026-05

Vitamin C Conditioning Generates Tumor-Targeting CAR T Cells with Superior Cytotoxicity and Fitness in a Posttransplant Lymphoproliferative Disorder Tumor Model.

Rahmati Pegah, Bonifacius Agnes, Dragon Anna Christina, Malinconico Chiara et al. — Molecular cancer therapeutics

Summary

This study found that treating CAR T cells with vitamin C significantly improves their ability to fight cancer. VitC conditioning led to a higher number of CAR T cells that were more effective at killing tumor cells, including those in a model for posttransplant lymphoproliferative disorder. These vitC-enhanced CAR T cells also showed better long-term performance and tumor-targeting capabilities, suggesting a promising new way to boost CAR T-cell therapy.

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Abstract

Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in hematologic malignancies but faces challenges in solid tumors and virus-associated malignancies such as posttransplant lymphoproliferative disorder (PTLD). Various strategies, including optimization of receptor design, genetic modifications addressing immunomodulatory mechanisms, and refining the manufacturing process, have been explored to overcome limited in vivo persistence and tumor infiltration, antigen escape, and the immunosuppressive tumor microenvironment. This study investigated the effect of vitamin C (vitC) conditioning on CD19-targeting CAR T cells (vitC-CAR19-T) to improve the efficacy of CAR T-cell therapy. VitC has been shown to influence immune responses through epigenetic regulation and oxidative stress reduction. Enhanced transduction efficiency and proliferative capacity by vitC conditioning resulted in a higher yield of CD4+ and CD8+ CAR19-Ts. VitC-CAR19-Ts exhibited faster and improved cytotoxic response toward CD19+ Nalm-6 cells and Epstein-Barr virus-infected B-lymphoblastoid cell lines, the in vitro model of PTLD. Increased demethylation was observed in TBX21 regions, which was in line with a type 1-like phenotype and higher expression of effector molecules such as granulysin in both CD4+ and CD8+ in vitC-CAR19-Ts, providing insights into the effects of vitC conditioning. Importantly, vitC-CAR19-Ts outperformed CAR19-Ts in long-term antigen stress assays and three-dimensional multicellular spheroid models, indicating a potentially improved in vivo functionality and tumor infiltration capacity. In summary, vitC conditioning represents a promising strategy to enhance CAR T-cell yield, cytotoxic potential, and durability, complementing existing approaches to overcome the limitations of CAR T cells in the treatment of hematologic malignancies and solid tumors.

View on PubMed →DOI: 10.1158/1535-7163.MCT-25-0005