The impact of hypoxia on oncolytic virotherapy

Abstract

Abstract:The hypoxic tumor microenvironment plays significant roles in tumor cell metabolism and survival, tumor growth, and progression. Hypoxia modulates target genes in target cells mainly through an oxygen-sensing signaling pathway mediated by hypoxia-inducible factor of transcription factors. As a result, hypoxic tumor cells are resistant to conventional therapeutics such as radiation and chemotherapy. Oncolytic virotherapy may be a promising novel therapeutic for hypoxic cancer. Some oncolytic viruses are better adapted than others to the hypoxic tumor environment. Replication of adenoviruses from both groups B and C is inhibited, yet replication of herpes simplex virus is enhanced. Hypoxia seems to exert little or no effect on the replication of other oncolytic viruses. Vaccinia virus displayed increased cytotoxicity in some hypoxic cancer cells even though viral protein synthesis and transgene expression were not affected. Vesicular stomatitis virus replicated to similar levels in both hypoxic and normoxic conditions, and is effective for killing hypoxic cancer cells. However, vesicular stomatitis virus and reovirus, but not encephalomyocarditis virus, are sensitive to elevated levels of hypoxia-inducible factor-1α in renal cancer cells with the loss of von Hippel-Lindau tumor suppressor protein, because elevated hypoxia-inducible factor activity confers dramatically enhanced resistance to cytotoxicity mediated by vesicular stomatitis virus or reovirus. A variety of hypoxia-selective and tumor-type-specific oncolytic adenoviruses, generated by incorporating hypoxia-responsive elements into synthetic promoters to control essential genes for viral replication or therapeutic genes, have been shown to be safe and efficacious. Hypoxic tumor-homing macrophages can function effectively as carrier cells to deliver an oncolytic adenovirus to the hypoxic/necrotic areas of the tumor. It is envisioned that further improved oncolytic viruses will be highly effective against hypoxic tumor, especially when combined with other therapeutic regimens such as immunotherapy, radiation therapy, and/or chemotherapy.

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

“…For example, oncolytic adenovirus replication is hampered under hypoxic conditions, while oncolytic HSV-1 replication is enhanced under hypoxic conditions. Oncolytic Vaccinia virus demonstrates improved cytotoxicity in hypoxic cancer cells, but has no increase in transgene expression [144]. Some studies have also demonstrated that inhibition of the mTOR pathway can also be detrimental for immunotherapy.…”

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

“…Recently, oncolytic virotherapy has garnered interest as potential therapeutic strategy for hypoxic tumors [29] . A hypoxia-responsive promoter that is upregulated by HIF-1 has been used for the tumor-specific replication of an oncolytic adenovirus [30] – [32] .…”

Revolutionizing cancer treatment: the power of bi- and tri-specific T-cell engagers in oncolytic virotherapy

“…The utilization of OVs in cancer therapy poses several challenges, including the issues of Limited Virus Penetration, patient selection, passive targeting, immune responses and hypoxia (100)(101)(102). In order to overcome these challenges that OV monotherapy is facing, today the attention of scientists in this field has been drawn to the genetic engineering of these viruses in order to express cytokines, chemokines, and also recombinant antibodies.…”