The oncolytic viral immunotherapy ASP1012 optimizes memory T cell responses after systemic delivery

Clinical use of oncolytic viral immunotherapies (OVIs) has been hindered by the requirement for intratumoral delivery and inconsistent activity. Here, we describe a novel, engineered strain of vaccinia virus (ASP1012) designed to overcome both limitations. ASP1012 displays improved systemic delivery even in the face of pre-existing anti-viral immunity. This is achieved through expression of the chemokine receptor CCR2, which, in turn, allows the virus to take advantage of inherent infection of lymphocytes in circulation and redirect these infected lymphocytes toward tumors expressing the chemokine CCL2, which is expressed by most solid human tumors. We have previously described potent T cell activation mediated by expression of the metabolic modulator leptin from an OVI. Here, we demonstrate significantly further increased therapeutic activity through expression of a Leptin-IL2 fusion protein and describe how this mediates changes in the tumor microenvironment leading to therapeutic activity in multiple mouse tumor models. ASP1012 expresses both CCR2 and Leptin-IL2, resulting in a therapy capable of producing complete responses in multiple mouse tumor models after intravenous delivery.