Systemic delivery of oncolytic vectors to treat metastatic disease

Intravenously administered oncolytic viruses cannot currently access established tumors at high levels because of virus neutralization, non-specific adhesion, active sequestration, mis-localization and vascular barriers. To extend our ongoing clinical trials, in which Reovirus is administered intravenously, we have now shown that pre-conditioning of C57B1/6 mice with PC-61-mediated Treg depletion and IL-2 enhances localisation of i.v. Reovirus to established tumors and generates significantly increased therapy compared to controls (p < 0.01). To develop clinically applicable protocols, we have also shown that cyclophosphamide (100mg/kg) functionally inhibits Treg activity. Consistent with this, pre-conditioning with CPA+IL-2 enhanced the therapy produced by systemic delivery of intravenously delivered, intermediate dose, Reovirus to a level indistinguishable from that induced by PC-61+IL-2, without any detectable toxicity. In addition, we have also developed cell carriers to carry viral vectors stealthily into the tumor. Adoptive transfer of antigen specific, T cells, pre-loaded with oncolytic viruses, protects virus from complement and antibody, delivers virus to tumors and generates significant therapy, which can be enhanced by increasing access of T cells into tumors by disrupting the tumor vasculature. In addition, cancer cells metastasize through the lymphatic system. We have developed protocols in which it is possible to chase these metastatic cells using immune cell types that home to the lymph nodes, such as naave T cells or dendritic cells. Thus, autologous cell carriers, pre-loaded with VSV or Reovirus, can purge LN and spleen of metastatic tumors through both direct viral oncolysis and priming of protective anti-tumor immunity. These studies provide the basis for clinical trials in which adoptive transfer of normal, lymph-node homing immune cells loaded with oncolytic virus will be used clinically for many common cancers in which the greatest risk to the patient stems from lymph node-disseminating metastatic cells.