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GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma

ABSTRACT: T-cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCKs) are engineered chimeric antigen receptor (CAR) T-cells that constitutively or inducibly release cytokines upon CAR engagement. Their purpose is to enhance the function of effector cells in the immune-suppressive tumor microenvironment (TME) of particularly solid tumors that is often devoid of pro-inflammatory cytokines. We capitalize on the pleiotropic effects of two γc family cytokines, interleukin (IL)-15 and IL-21, and use them synergistically for TRUCK engineering. We demonstrate that TRUCKs with soluble IL-15/IL-21 eradicate CAR T-cell–resistant neuroblastoma, the most common extra-cranial solid tumor of childhood, but are associated with significant toxicities in mice. These toxicities can be delayed when we constitutively tether the cytokines to the surface of T-cells but are abrogated when we engineer CAR T-cells with NFAT-induced membrane-tethered IL-15/IL-21 expression.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE243349 | GEO | 2025/06/17

REPOSITORIES: GEO

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