Engineering CAR-Vδ2 T cells to boost persistence and anti-tumor function

Area of Science:

• Immunology
• Cell Therapy
• Cancer Research

Background:

• Chimeric antigen receptor (CAR)-modified Vδ2 T cells show promise for cancer immunotherapy.
• Clinical efficacy is limited by short *in vivo* persistence and susceptibility to activation-induced cell death (AICD).
• Insufficient cytokine support contributes to limited T cell persistence.

Purpose of the Study:

• To enhance the *in vivo* persistence and anti-tumor activity of CAR-Vδ2 T cells.
• To identify membrane-bound cytokines supporting superior CAR-Vδ2 T cell function.
• To develop a strategy for antigen-driven IL-18 signaling and AICD resistance.

Main Methods:

• Comparison of membrane-bound (mb) cytokines to identify optimal support for CAR-Vδ2 T cells.
• Fusion of MyD88 (IL-18R signaling mediator) to an extracellular Fas domain (Fas88) for antigen-driven signaling.
• Evaluation of Fas88-armed CAR-Vδ2 T cells in xenograft models of hematologic and solid malignancies.

Main Results:

• Membrane-bound IL-18 (mbIL-18) demonstrated superior anti-tumor activity for CAR-Vδ2 T cells *in vitro* and *in vivo*.
• Fas88 fusion enabled antigen stimulation-induced IL-18 signaling and protected Vδ2 T cells from AICD.
• Fas88-armed CAR-Vδ2 T cells exhibited superior, stimulation-dependent *in vivo* expansion and functional persistence.

Conclusions:

• IL-18 signaling and AICD resistance are critical for CAR-Vδ2 T cell efficacy.
• A single-transgene modification using Fas88 enhances CAR-Vδ2 T cell activity.
• This strategy limits inflammatory risk and facilitates clinical translation of CAR-Vδ2 T cell therapy.