Using charge-altering releasable transporters (CARTs), Haabeth and Blake et al. found that the combined intratumoral delivery of OX40L, CD80, and CD86, or OX40L and IL-12 mRNA led to eradication of injected A20 lymphomas in most mice, eradication of both injected and distal tumors in 40% of mice, increased survival, and establishment of immunological memory. OX40L/CD80/CD86 delayed tumor growth in uncured mice better than OX40L/IL-12. The systemic effect was attributed to local activation and mobilization of tumor-specific immune cells, which migrated to the local draining lymph node and to distant tumors.
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.
Author Info: (1) Department of Medicine, Division of Oncology, Stanford University. (2) Chemistry, Stanford. (3) Chemistry, Stanford. (4) Dept. of Immunology and Transfusion Medicine, Universit
Author Info: (1) Department of Medicine, Division of Oncology, Stanford University. (2) Chemistry, Stanford. (3) Chemistry, Stanford. (4) Dept. of Immunology and Transfusion Medicine, University of Oslo. (5) Department of Medicine, Division of Oncology, Stanford University. (6) Chemistry, Stanford. (7) Chemistry, Stanford. (8) Division of Oncology, Stanford University Hospital and Clinics levy@stanford.edu.
