Exploiting tumor epigenetics to improve oncolytic virotherapy

Abstract

Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.

Overcoming Barriers in Oncolytic Virotherapy with HDAC Inhibitors and Immune Checkpoint Blockade

“…This approach is supported by recent studies showing that synergistic anti-cancer effects can be achieved through rationally designed therapies combining OVs with other anti-cancer agents. The wide repertoire of novel anti-cancer therapeutics developed thus far ranges from signalling pathway inhibitors [ 56 ], to epigenetic modulators [ 60 ], TME modifiers and various forms of immunotherapy [ 20 ] thereby providing a number of different strategies with which to manipulate, and hopefully increase the success of oncolytic virotherapy. Combination regimens under investigation aim to: (i) improve systemic OV delivery [ 9 ]; (ii) enhance intratumoural OV spread by increasing viral entry, replication or diffusion between neighbouring cells [ 9 ]; (iii) augment direct OV-mediated cytotoxicity [ 9 ]; and (iv) enhance the anti-tumour immune response elicited during OV therapy [ 61 ].…”

Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma

“…To address this heterogeneity in tumor cell susceptibility toward oncolytic virotherapy, HDACi can be employed to repress innate immunity signaling with restriction to malignant cells. 43 Interestingly, HDACi were found to have the potency to undermine antiviral immunity resulting in enhanced OV replication. 13 Mechanistically, inhibition of HDAC activity by TSA was found to inhibit IFN-β production, and silencing of HDAC6 was correlated with an increased replication of VSV.…”

Collective Population Effects in Nonviral Systems

“…This two-component theory is reminiscent of the "pan-genome" concept in bacteria. Tumor cell heterogeneity represents also a limitation to the efficacy of oncolytic viruses (Forbes et al, 2013). The genome complement of the bacterial species as a whole is larger than the genome portion present in individual strains within the species.…”