Genetically Engineered Vaccinia Viruses As Agents for Cancer Treatment, Imaging, and Transgene Delivery

Abstract

Despite advances in technology, the formidable challenge of treating cancer, especially if advanced, still remains with no significant improvement in survival rates, even with the most common forms of cancer. Oncolytic viral therapies have shown great promise for the treatment of various cancers, with the possible advantages of stronger treatment efficacy compared to conventional therapy due to higher tumor selectivity, and less toxicity. They are able to preferentially and selectively propagate in cancer cells, consequently destroying tumor tissue mainly via cell lysis, while leaving non-cancerous tissues unharmed. Several wild-type and genetically engineered vaccinia virus (VACV) strains have been tested in both preclinical and clinical trials with promising results. Greater understanding and advancements in molecular biology have enabled the generation of genetically engineered oncolytic viruses for safer and more efficacious treatment, including arming VACVs with cytokines and immunostimulatory molecules, anti-angiogenic agents, and enzyme prodrug therapy, in addition to combining VACVs with conventional external and systemic radiotherapy, chemotherapy, immunotherapy, and other virus strains. Furthermore, novel oncolytic vaccinia virus strains have been generated that express reporter genes for the tracking and imaging of viral therapy and monitoring of therapeutic response. Further study is needed to unlock VACVs' full potential as part of the future of cancer therapy.

Keywords: gene therapy; molecular imaging; oncolytic viral therapy; vaccinia virus.

Figure 1

Overview of new oncolytic vaccinia virus generations.

Figure 2

Molecular imaging of oncolytic vaccinia virus GLV-1h153. (A) GLV-1h153 construct. GLV-1h153 was derived from LIVP-wt virus, by replacing the gusA expression cassette at the A56R locus with the human sodium iodide symporter (hNIS) expression cassette through homologous recombination. The virus also contains RUC-green fluorescent protein (GFP) and lacZ expression cassettes at the F14.5L and J2R loci, respectively. PE, PE/L, P11, and P7.5 are the vaccinia virus synthetic early, synthetic early/late, 11K, and 7.5K promoters, respectively. TFR is a human transferrin receptor inserted in the reverse orientation with respect to the promoter PE/L. (B) GFP, bioluminescence, and hNIS signal could be detected in GLV-1h153-infected tumors. Fusion of PET and CT images correlated hNIS-mediated uptake signal anatomically to location of thyroid and stomach due to intrinsic hNIS expression, bladder due to radiotracer excretion, and tumor due to virus-mediated hNIS expression. Virally-mediated GFP and bioluminescence signals located only to tumor, demonstrating tumor-specific viral replication.