Overcoming extracellular vesicle-mediated fratricide improves CAR T cell treatment against solid tumors

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows limited efficacy against solid tumors.
• Mechanisms of CAR T cell resistance in solid tumors are not fully understood.
• Novel strategies are needed to enhance CAR T cell function and overcome resistance.

Purpose of the Study:

• To elucidate the molecular mechanisms of CAR T cell resistance in solid tumors.
• To develop and evaluate engineered CAR T cells with improved anti-tumor activity.
• To investigate the potential of Serpin B9 as a protective agent against CAR T cell fratricide.

Main Methods:

• Analysis of extracellular vesicle secretion by solid tumors in response to CAR T cells.
• Horizontal transfer of tumor antigens from extracellular vesicles to CAR T cells.
• Engineering CAR T cells with Serpin B9, a granzyme B inhibitor.
• In vivo studies using female mice to assess CAR T cell vitality, tumor infiltration, and anti-tumor activity.
• Combination therapy with Serpin B9-armored CAR T cells and anti-programmed death 1 antibody.

Main Results:

• Solid tumors upregulate small extracellular vesicles carrying tumor antigens, leading to CAR T cell fratricide.
• Engineered CAR T cells armored with Serpin B9 exhibit reduced fratricide and enhanced vitality.
• Serpin B9-armored CAR T cells demonstrate improved tumor infiltration and anti-tumor activity in vivo.
• Combination therapy of Serpin B9-armored CAR T cells with anti-PD-1 antibody shows superior efficacy in treating solid tumors.

Conclusions:

• Horizontal transfer of tumor antigens via extracellular vesicles induces CAR T cell fratricide, limiting efficacy against solid tumors.
• Armoring CAR T cells with Serpin B9 effectively mitigates fratricide, boosting their anti-tumor functions.
• Serpin B9-armored CAR T cells represent a promising therapeutic strategy for solid tumors, especially when combined with immune checkpoint inhibitors.