Combining Oncolytic Viruses with Epigenetic Modifiers to Treat Acute Lymphocytic Leukemias
Acute leukemias are aggressive cancers of the cells of the blood. Current therapies are intensive and have devastating, often permanent side-effects, and responses are variable. For patients that do respond to current therapies, relapse is common. Pursuit of novel therapies for leukemias is warranted. While oncolytic viruses and epigenetic modifiers have limited efficacy as monotherapies for acute leukemias, we found that combining these therapies led to enhanced efficacy in murine models of acute T and B lymphocytic leukemias. Histone deacetylase inhibitors and DNA-methyltransferase inhibitors were successfully combined with maraba virus (MG1), vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV). Enhanced efficacy was observed using the epigenetic modifiers to potentiate the effects of oncolytic viruses, and oncolytic viruses were also used to enhance the efficacy of epigenetic modifiers. Both protocols led to remissions using the EL-4 murine model of T-cell acute lymphocytic leukemia. Overall these combinations of therapies appear to have superior efficacy in the EL-4 model of T cell acute lymphocytic leukemia when compared with the L1210 B-cell acute lymphocytic leukemia model. The use of the DNA methyltransferase inhibitor decitabine conferred the greatest benefits when compared with MS275, a histone deacetylase inhibitor. The combination of decitabine followed with vesicular stomatitis virus was the optimal therapeutic protocol tested. Using this combination of therapies, remissions were achieved in over 70% of mice. Furthermore, when re-challenged with a second dose of EL-4 cells on day 60, all the mice resisted the induced relapse scenario (re-exposure to cancer cells), suggesting immunological memory was established. Investigation of the EL-4 cells that survived decitabine therapy revealed that they chronically produced increased reactive oxygen species. Further investigation into the NDV-surviving EL-4 cells revealed they also produced greater amounts of reactive oxygen species. Removal of these reactive oxygen species with N-acetyl-L-cysteine was found to rescue the cells from the combination effects of our protocol. Overall, the results indicate that reactive oxygen species play an important mechanistic role in the enhanced efficacy against leukemias that can be achieved by combining oncolytic viruses with epigenetic modifiers.