CAR-T 细胞作为抗实体瘤微药房：在一步工程化过程中结合效应 T 细胞介导的细胞死亡与血管靶向

To enhance the potency of chimeric antigen receptor (CAR) engineered T cells in solid cancers, we designed a novel cell-based combination strategy with an additional therapeutic mode of action. CAR T cells are used as micropharmacies to produce a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR, which exerts pro-coagulatory activity and hypoxia upon relocalization to the vascular endothelial cells that invade tumor tissues. Delivery by CAR T cells aimed to induce locoregional tumor vascular infarction for combined immune-mediated and hypoxic tumor cell death.

Human T cells that were one-vector gene-modified to express a G D2 -specific CAR along with CAR-inducible tTF-NGR exerted potent G D2 -specific effector functions while secreting tTF-NGR that activates the extrinsic coagulation pathway in a strictly G D2 -dependent manner.

In murine models, the CAR T cells infiltrated G D2 -positive tumor xenografts, secreted tTF-NGR into the tumor microenvironment and showed a trend towards superior therapeutic activity compared with control cells producing functionally inactive tTF-NGR. In vitro evidence supports a mechanism of hypoxia-mediated enhancement of T cell cytolytic activity.

We conclude that combined CAR T cell targeting with an additional mechanism of antitumor action in a one-vector engineering strategy is a promising approach to be further developed for targeted treatment of solid cancers.