Abstract

Localized expression of effector molecules can initiate anti-tumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic anti-tumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for co-stimulatory and immune-modulating factors. Intratumoral injection of the CART-mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local anti-tumor effect. Using a two-tumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic anti-tumor response, curing both tumors. The combination of OX40L-, CD80-, and CD86-encoding mRNA resulted in the local upregulation of pro-inflammatory cytokines, robust local T cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic anti-tumor immunity from a single localized injection.

View details for PubMedID 30692215