CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process
Bianca Altvater, Sareetha Kailayangiri, Christian Spurny, Maike Flügge, Jutta Meltzer, Lea Greune, Katja Urban, Christian Schwöppe, Caroline Brand, Christoph Schliemann, Heike Hintelmann, Saliha Harrach, Wolfgang Hartmann, Hinrich Abken, Johannes Kuehle, Axel Schambach, Dennis Görlich, Wolfgang E. Berdel, Claudia Rössig
Abstract
Abstract 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.