Oncolytic Virotherapy

Is it possible to turn viruses into living organism that can kill cancer cells? Is that so, how its mechanism of action can be? I'm going to reveal all the mechanisms briefly behind these questions.

Firstly, we need to know what exactly oncolytic viruses (OVs) are. This cancer-targeted viruses are genetically modified that selectively lyse tumor cells without intruding normal cells. The general mechanisms of oncolysis is that OVs can penetrate cells through plasma membrane by fusion or binding the surface's receptor. The prominent characteristic that an OV has the capability to differentiate the cancer cells and begin to lytic them, either by the activation of RAS pathway or by genetic remodeling.[1]

Talimogene laherparepvec (T-VEC, Imlygic R) is the first genetically engineered herpes simplex virus type 1 (HSV-1) which administered by interlesional injection through cutaneous, subcutaneous or nodal location.[2] It used for the treatment of unresectable metastatic stage IIIB/C-IVM1a melanoma.[3]

The mechanism of T-VEC

It has been shown that the HSV-1 have two deleted genes, to be exact is at ICP34.5 which in turn enhancing the selectivity of tumor cells replication and ICP47 which responsible for enhancing anti-tumor characteristics by inhibits ICP47 from blocking antigen presentation. Furthermore, two copies of the human GM-CSF gene are inserted into the virus with the cytomegalovirus promoter help, which amplify high levels of expression. It leads to maturation and recruitment of dendritic cells therefore improving the immune response during oncolysis.[4]

The figure 1 depicts the proposed mechanisms of action of T-VEC at two different site actions (locally and systematically). The viral replication after the injection will then release the progeny viruses to target and infect other local tumor cells, which in turn the cycle is repeated.[5]

Result

The picture below illustrates that T-VEC has shown efficacy in treating advanced melanoma.[6]

The second OVs is being under development by Imungene Limited called CF33-hNIS (VAXINIA) and is in the phase I (dose escalation safety and tolerability study). VAXININA is a chimeric orthopoxvirus (a virus that causes smallpox) which can be given as monotherapy or in combination with Pembrolizumab in adults with metastatic or advaced solid tumors (MAST).[7] What interesting about VAXINIA is that it is highly cytolytic for a broad range of tumor cell types so it potentially act as a gene therapy and oncolytic agent at the same time. Hope this drug development could be an innovator of more gene therapy development in the future.

References

[1] Fountzilas, C., Patel, S., & Mahalingam, D. (2017). Oncolytic virotherapy, updates and future directions. Oncotarget, 8(60), 102617.

[2] O'Donoghue, C., Doepker, M. P., & Zager, J. S. (2016). Talimogene laherparepvec: overview, combination therapy and current practices. Melanoma Management, 3(4), 267-272.

[3] European Medicines Agency. (2015) Imlygic International non-proprietary name: talimogene laherparepvec.

[4] Liu, B. L., Robinson, M., Han, Z. Q., Branston, R. H., English, C., Reay, P., ... & Coffin, R. S. (2003). ICP34. 5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene therapy, 10(4), 292-303.

[5] Harrington, K. J., Puzanov, I., Hecht, J. R., Hodi, F. S., Szabo, Z., Murugappan, S., & Kaufman, H. L. (2015). Clinical development of talimogene laherparepvec (T-VEC): A modified herpes simplex virus type-1–derived oncolytic immunotherapy. Expert review of anticancer therapy, 15(12), 1389-1403.

[6] Haitz, K., Khosravi, H., Lin, J. Y., Menge, T., & Nambudiri, V. E. (2020). Review of talimogene laherparepvec: A first-in-class oncolytic viral treatment of advanced melanoma. Journal of the American Academy of Dermatology, 83(1), 189-196.

[7] NIH, 2022, A Study of CF33-hNIS (VAXINIA), an Oncolytic Virus, as Monotherapy or in Combination With Pembrolizumab in Adults With Metastatic or Advanced Solid Tumors (MAST), https://clinicaltrials.gov/ct2/show/NCT05346484, accessed on 8th of June 2022.