Year: 2026
Type: preprint
Abstract: Chimeric antigen receptor (CAR)-modified Vδ2 T cells are an attractive therapeutic cell platform for cancer immunotherapy. However, their clinical efficacy is limited by short in vivo persistence due to insufficient cytokine support and high susceptibility to activation-induced cell death (AICD). Through comparison of membrane-bound (mb) cytokines, we identified mbIL-18 to support superior anti-tumor activity of CAR-Vδ2 T cells in vitro and in vivo . To reduce constitutive surface exposure of IL-18 and enable antigen-driven signal 3, we fused MyD88 - the key IL-18R signaling mediator - to an extracellular domain of Fas (Fas88). Antigen stimulation-induced FasL engagement of Fas88 triggered IL-18 signaling while simultaneously protecting Vδ2 T cells from AICD. Fas88-armed human CAR-Vδ2 T cells produced superior yet stimulation-dependent in vivo expansion and functional persistence in xenograft models of hematologic and solid malignancies. Together, these findings highlight the importance of IL-18 signaling and AICD resistance for CAR-Vδ2 T cell activity, enabling a single-transgene modification to limit inflammatory risk and facilitate clinical translation.
Authors: Leonard Leong, Mansi Narula, Johannes Englisch, Cheryl Ou, Maksim Mamonkin, Norihiro Watanabe
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1411362006, SPORE in Lymphoma
OpenAlex ID: W7154512451
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