Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert “immune-cold” tumors to “immune-hot” will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.

Oncolytic viruses are one of the most promising novel therapeutics for malignant cancers. They selectively infect and kill cancer cells while sparing the normal counterparts, expose cancer- specific antigens and activate the host immune system against both viral and tumor determinants. Oncolytic viruses can be used as monotherapy or combined with existing cancer therapies to become more potent. Among the many types of oncolytic viruses that have been developed thus far, members of poxviruses are the most promising candidates against diverse cancer types. This review summarizes recent advances that are made with oncolytic myxoma virus (MYXV), a member of the Leporipoxvirus genus. Unlike other oncolytic viruses, MYXV infects only rabbits in nature and causes no harm to humans or any other non-leporid animals. However, MYXV can selectively infect and kill cancer cells originating from human, mouse and other host species. This selective cancer tropism and safety profile have led to the testing of MYXV in various types of preclinical cancer models. The next stage will be successful GMP manufacturing and clinical trials that will bring MYXV from bench to bedside for the treatment of currently intractable malignancies.

Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties—oncolytic and immune response-boosting effects—have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes murine LIGHT, also called tumor necrosis factor ligand superfamily member 14 (TNFSF14). The viability and proliferation of ADSCs were not remarkably decreased (1–2 days) following MYXV infection, in sharp contrast to cells of pancreatic carcinoma lines studied, which were rapidly killed by the infection. Comparison of the intraperitoneal (IP) vs. the intravenous (IV) route of ADSC/MYXV administration revealed more pancreas-targeted distribution of the virus when ADSCs were delivered IP to mice bearing orthotopically injected PDAC. The biodistribution, tumor burden reduction and anti-tumor adaptive immune response were examined. Bioluminescence data, used to assess the presence of the luciferase-tagged virus after IP injection, indicated enhanced trafficking into the pancreata of mice bearing orthotopically-induced PDAC, as compared to tumor-free animals, resulting in extended survival of the treated PDAC-seeded animals and in the boosted expression of key adaptive immune response markers. We conclude that ADSCs pre-loaded with transgene-armed MYXV and administered IP allow for the effective ferrying of the oncolytic virus to sites of PDAC and mediate improved tumor regression.

Oncolytic viruses (OVs) have emerged as one of the most promising cancer immunotherapy agents that selectively target and kill cancer cells while sparing normal cells. OVs are from diverse families of viruses and can possess either a DNA or an RNA genome. These viruses also have either a natural or engineered tropism for cancer cells. Oncolytic DNA viruses have the additional advantage of a stable genome and multiple-transgene insertion capability without compromising infection or replication. Herpes simplex virus 1 (HSV-1), a member of the oncolytic DNA viruses, has been approved for the treatment of cancers. This success with HSV-1 was achievable by introducing multiple genetic modifications within the virus to enhance cancer selectivity and reduce the toxicity to healthy cells. Here, we review the natural characteristics of and genetically engineered changes in selected DNA viruses that enhance the tumor tropism of these oncolytic viruses.

The cellular DHX9 has both proviral and antiviral roles against diverse RNA and DNA viruses. In this article, we demonstrate that DHX9 can form unique antiviral granules in the cytoplasm during myxoma virus (MYXV) replication in human cancer cells.

The Yatapoxviruses encode a distinct class of secreted TNF-binding protein (TNF-BP) that resembles an MHC class I heavy chain but distinct from any other known TNF inhibitor. Characterization of these viral TNF inhibitors from Tanapox virus, Yaba monkey tumor virus (YMTV) and a closely related version from Swinepox virus revealed dramatically differential TNF binding specificities for different mammalian species. The Tanapox virus 2L protein (TPV-2L) formed inhibitory complexes with human TNF, and interacted with monkey and canine TNF with high affinity but rabbit TNF with low affinity. On the other hand, YMTV-2L bound human and monkey TNF with high affinity but rabbit TNF with only low affinity. The TNF-BP from swinepox virus (SPV003/148) only interacted with porcine TNF with high affinity. The observed TNF binding analysis mirrored the biological activity of these TNF-binding protein to block TNF-induced cellular cytolysis. TPV-2L and YMTV-2L also inhibited the human TNF-mediated signaling in cells but TPV-2L exhibited higher affinity for human TNF (KD, 43 pm) compared with monkey (KD, 120 pm) whereas for YMTV-2L, the affinities were reversed (human TNF KD, 440 pm; monkey TNF KD, 230 pm). The interaction domain of human TNF with TNF-binding proteins is significantly different from that of TNFRs, as determined using human TNF mutants. We conclude that these poxvirus TNF-binding proteins represent a new class of TNF inhibitors and are distinct from the viral TNF receptor homologues characterized to date.