M1-c6v1 developed by Virotech is a genetically engineered virus strain based on the dominant clone sequence of the wild-type M1 virus.
It is a genetically modified oncolytic virus belonging to the Alphavirus genus (alphavirus M1) of the Togaviridae family.
Mechanisms of M1 that exert antitumor effects:
1、infection and replication within cancer cells, resulting in direct cell lysis and cell death via apoptosis or autophagic cell death
2、release of cytokines by infected cells, promoting the death of surrounding cancer cells
3、triggering of immune responses to antigens on the dead cancer cells, which enhance systemic antitumor effects.
Types of M1 oncolytic alphavirus antitumor Effects
Oncolytic viruses specifically replicate and spread within cancer cells, resulting in direct cell lysis and different forms of cell death, including apoptosis, or autophagic cell death. This mechanism is involved in the antitumor effects of almost all oncolytic viruses and is also fundamental to the further activation of immune response . To enhance the direct oncolytic effect, oncolytic viruses can be armed with pro-apoptotic factors or co-administered with cytotoxic chemotherapy agents or pro-apoptotic molecularly targeted drugs.
In cancer cells infected by oncolytic viruses, the antiviral immune response is frequently activated, leading to the production of many antiviral and inflammatory factors . These factors bind to the membrane receptors expressed on surrounding cancer cells to promote cell death, and recruit immune cells to the infected site, mediating antiviral and antitumor effects on those uninfected tumor cells . This so-called “bystander killing effect” has been found to be an important antitumor mechanism for a few oncolytic viruses, such as vesicular stomatitis virus and M1.
Selectivity of M1 virus
Various cytological characteristics of tumor cells have been identified that contribute to the selectivity of M1 virus for tumor cells rather than normal cells. The two major factors are low expression of the antiviral protein ZAP and activating mutations in the Ras proto-oncogene pathway that sensitize cancer cells to M1 infection and lysis. Both down-regulation of ZAP and activating mutations in the Ras proto-oncogene pathway are prevalent in a high proportion of human cancers. Ultimately, the failure of tumor cells to activate interferon (IFN) signaling pathways in response to M1-c6v1 makes them susceptible to M1-c6v1 infection and lysis.
The cytological characteristics of tumor cells, such as low expression of the antiviral protein ZAP, determine the cell selectivity of M1 viruses for tumor cells rather than normal cells.
M1– VCP inhibitor combination therapy enhance the specificity, cytotoxicity or immune-stimulating potential of the virus. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus.
Valosin-containing protein (VCP, also known as transitional endoplasmic reticulum ATPase) inhibitors cooperate with M1 virus to trigger irresolvable endoplasmic reticulum stress and apoptosis in hepatocellular carcinoma cells.
a) In untreated cells, the accumulation of unfolded proteins leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR), which in turn eliminates malformed proteins to relieve ER stress and restore proper ER function. M1 virus infection causes suppression of the inositol-requiring enzyme 1α (IRE1α)–X‑box-binding protein 1 (XBP1) pathway, although low concentrations are not sufficient to induce severe ER stress.
b) When M1 infection occurs in the presence of valosin-containing protein (VCP) inhibitors, the IRE1α–XBP1 pathway is suppressed, causing overload of the UPR, which leads to irresolvable ER stress and subsequent apoptosis.
Liposome encapsulation of oncolytic virus M1
Encapsulating oncolytic virus M1 in liposomes may reduce intrinsic viral immunogenicity and immune clearance in vivo for improved anticancer therapy.
Synergistic targets within the M1 virus anti-tumour multiple pathways
Virotech focuses on the development of innovative genetically engineered oncolytic alphavirus for cancer treatment, oncolytic virus synergists and in preparation of anti-tumour drugs since it was founded. Recently, our product portfolio has expanded to include in vitro diagnostics kits.
Virotech is planning to initiate Phase I clinical trial in Australia, and submit INDs in US and China in early 2021.