Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery

摘要

Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues. What's new? Immunological tolerance of tumor cells is a major obstacle to efficient cancer prevention and treatment. Engrafting T cells with chimeric antigen receptors (CARs) increases the number of high-affinity tumor-specific T cells in an attempt to tackle tumor tolerance therapeutically. Current CAR strategies exclusively target tumor cells, but here the authors report the construction of eCAR that targets tumor blood vessels instead thus overcoming the difficulty of CAR-modified T cells to penetrate tumor parenchyma. They show that T cells engrafted with eCAR (T-eCAR) can efficiently lyse umbilical vein endothelial cells and that its in vivo administration results in significant tumor shrinkage. Moreover, delivery of T-eCAR together with nanoparticles increases the tumor deposition of the latter, pointing to a new combinatorial strategy for selective anticancer drug delivery.