RE:RE:CellPress: Emerging Field of OV Based Cancer ImmunotherapyThe oncolytic virus reovirus (pelareorep) has demonstrated that it can convert cold tumors into "hot" tumor by overcoming a hostile (hypoxic) tumor microenvironment (TME) and turning such a hostile TME into one that is more conducive for treatment with immune checkpoint inhibitors, like Roche's atezolizumab (Tecentriq), or Merck KGaA/Pfier's avelumab (Bavencio), or Incyte's retifanlimab, as several examples.
Simply, the tumor microenvironment (TME) is the ecosystem around tumor or cancer stem cells. A growing number of studies are emphasizing the importance of TME in recurrence, metastasis, and the development of drug resistance by cancer cells. TME comprises blood vessels, lymph vessels, immune cells, and proliferating tissue. One of the major features of the TME in solid tumors is hypoxia, which has been defined as a state in which adequate oxygen is not available.
There are two types of hypoxic conditions. First, diffusion-limited hypoxia or chronic hypoxia leads to inhibition of cell proliferation in cancer regions with low oxygen concentration and the hypoxic microenvironment is a major limitation that affects the efficacy of many oncolytic viruses, other than reovirus (pelareorep).
In demonstrating the effect of reovirus (pelareorep) on the TME Carew et al. demonstrated that Pelareorep (unmodified human reovirus) could down-regulate HIF-1, HIF-2, and VEGF expression. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to hypoxia. HIF has been shown to be one of the modulators of host cell innate immune response to virus infection by over-expression of interferons (IFNs) and other gene transcripts with anti-viral activity. Hence, down-regulation of HIF can improve oncolytic therapy against various types of tumors.
In pre-clinical studies dating back to 2010 researchers found that reovirus (pelareorep) could replicate in and lyse cancer cells under hypoxic environments and in the process induce apoptosis in those cancer cells.
Aligned with this prior research, Hotani et al. demonstrated that at 120 h post-systemic administration of RV, HIF-1 and its target genes were down-regulated. In addition, they inactivated RV by UV and observed that the HIF-1 protein level was not altered, proposing that HIF-1 down-regulation was dependent on RV replication.
Additionally Hotani et al. investigated the replication of RV in the hypoxic region of tumors, and found the RV capsid protein in the hypoxic region of tumors 120 h after systemic administration of RV indicating RV's ability to overcome the hostile TME while "priming" the innate and adaptive immune system for the administration of immune checkpoint inhibitors, like those referenced above.