T_STEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in...

Area of Science:

• Immunology
• Cell Biology
• Cancer Therapy

Background:

• Chimeric antigen receptor (CAR)-T cell therapy efficacy relies on T cell memory and persistence.
• Stem-like CD8+ memory T cell progenitors can differentiate into functional TSTEM cells or exhausted TPEX cells.
• Previous CAR-T cell products showed limited TSTEM cell abundance and poor patient persistence.

Purpose of the Study:

• To develop a protocol for generating TSTEM-like CAR-T cells with enhanced proliferative capacity and persistence.
• To evaluate the therapeutic efficacy of TSTEM-like CAR-T cells in preclinical cancer models.

Main Methods:

• Developed a novel CAR-T cell production protocol to enrich for TSTEM-like cells.
• Assessed CAR-T cell proliferation, cytokine secretion, and persistence in vitro and in vivo.
• Utilized preclinical models to evaluate tumor control and survival after TSTEM-like CAR-T cell adoptive transfer.
• Investigated the combination of TSTEM-like CAR-T cells with anti-programmed cell death protein 1 (PD-1) therapy.

Main Results:

• TSTEM-like CAR-T cells exhibited enhanced proliferative capacity and cytokine secretion compared to conventional CAR-T cells.
• Production of TSTEM-like CAR-T cells was dependent on the presence of CD4+ T cells.
• Adoptive transfer of TSTEM-like CAR-T cells led to superior tumor control and resistance to tumor rechallenge in preclinical models.
• TSTEM-like CAR-T cells demonstrated increased persistence and expanded the memory T cell pool in vivo.
• Combination therapy with TSTEM-like CAR-T cells and anti-PD-1 eradicated tumors, increasing tumor-infiltrating CD8+CAR+ T cells producing interferon-γ.

Conclusions:

• The developed CAR-T cell protocol successfully generates TSTEM-like CAR-T cells with improved therapeutic efficacy.
• TSTEM-like CAR-T cells possess enhanced proliferative capacity and in vivo persistence, leading to better disease control.
• This approach holds promise for improving CAR-T cell therapy outcomes in cancer patients.