How an oncolytic virus could theoretically work
To replicate inside a normal cell, a virus needs to first block the cell’s antiviral responses. Such anti-viral response pathways are often already disabled in cancer cells (). The process of making a virus oncolytic , i.e., tumor-killing, exploits this difference in kind (see figure on left below from 2). As well, cancer cells often have genetic dysregulation, such as activation of the Ras oncogene pathway, that further support viral replication. Oncolytic viral replication in cancer cells eventually triggers their death. This releases tumor-specific antigens, which serve as a beacon and focus of anti-tumor-specific immune responses.
So oncolytic virus Rx can be seen as a one-two punch. First, the virus infects some cancer cells, replicates within and kills them. Ensuing damage serves as the impetus for tumor-specific immune response, effective both locally as well as systemically. Though compelling in theory, to be successful, oncolytic virus Rx has to overcome both systemic and local barriers, which can rapidly clear it from the body (; see figures on right below from ). Given it is a live virus Rx, safety is an overarching concern as well, i.e., as much as possible ensure virus selectively infects and damages tumor alone (oncotropism). These constraints make the process of developing safe but effective oncolytic viruses extremely challenging.
- Naturally occurring Oncolytic viruses. Myxoma virus, Newcastle disease virus, reovirus and VSV (vesicular stomatitis virus) can infect human cells but generally cannot replicate within them because they don’t encode anti-viral response-blocking genes. Thus, such viruses can replicate more easily in tumor but not in normal cells.
- Genetically engineered Oncolytic viruses. OTOH, herpes and adeno viruses can specifically block the cell’s antiviral response. Such viruses can thus replicate in normal cells. However, selectively removing such viral genes renders these viruses able to replicate in tumor but not normal cells.
State of the art in oncolytic virus therapy research: In October 2015, Imlygic/talimogene laherparepvec (T-VEC) became the first EMA (European Medicines Agency)- and FDA-approved oncolytic virus therapy, specifically for melanoma in patients with inoperable tumors.
What is T-VEC?
- Derived from an employee’s cold sore and modified to target cancer cells ( , 6, ; See figures below from and 9), T-VEC and its maker, the Massachusetts, USA-based BioVex, were acquired by Amgen in 2011.
- T-VEC’s derived from HSV-1 (Herpes Simplex Virus 1).
- Both copies of ICP34.5 (infected cell protein 34.5) deleted.
- ICP34.5 is HSV-1’s neurovirulence protein, necessary to infect neurons and other healthy cells.
- Binds to and blocks cell’s PKR (Protein Kinase R), and enables viral replication.
- Deletion renders virus incapable of replication in healthy cells.
- Viral mutants were serially passaged through cancer cells to improve their cancer cell-killing ability
- A spontaneous mutant (translocation of the US11 gene) better killed a variety of cancer cell lines.
- Turned out US11 gene translocation was linked to deletion of ICP47, a viral gene that limits antigen presentation, a common viral mechanism to evade immune response. ICP47 deletion enhances tumor cell antigen presentation
- Scientists inserted human gene encoding GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) into T-VEC.
- T-VEC-infected tumor cells secrete GM-CSF, a cytokine that’s a DC (Dendritic Cell) growth factor.
- GM-CSF should induce DC accumulation in tumor’s vicinity and jumpstart tumor-specific immune response as T-VEC-infected tumor cells start dying.
How T-VEC is used and how it might work (see figure below from)
- Directly injected into melanoma lesions (in/under the skin or into nodes) at doses of up to 4ml of 10 6 to 10 8 pfu (plaque forming units)/ml.
- T-VEC may selectively replicate in tumor cells and lyse them.
- Tumor cell death releases tumor antigens as well as more virus which can infect more tumor cells.
- T-VEC also expresses GM-CSF, a cytokine that’s a growth factor for DCs (dendritic cells), key cells in getting adaptive (T and B cell) immune responses started.
- GM-CSF induces local DC accumulation.
- DCs ingest dead/dying tumor cells, process and present tumor antigens locally to tumor-specific T cells, thus triggering specific anti-tumor immune responses.
T-VEC Trial Data (see tables below from 11)
- A Phase II clinical trial (NCT00289016; ): 50 patients treated with T-VEC every 3 weeks. 13 patients responded (26%) of whom 12 were alive 1 year after starting Rx.
- A Phase III clinical trial (NCT00769704; ) of 295 patients randomized 2:1 to get either T-VEC or GM-CSF Rx had median survival of 23.3 versus 19 months.
These data suggest modest but consistent improved survival with T-VEC in late stage (III and IV) melanoma. Improvement in late stage disease makes the data compelling. Also promisingly, adverse effects were mild, mainly amounting to mild flu-like symptoms.
Oncolytic virus for prostate cancer
A variety of engineered viruses are being tested in preclinical mouse prostate cancer models. These include Adeno, Herpes (), Newcastle disease ( ), Reo (14) and VSV ( ). Main problem is promising mouse model results fail to translate to humans. Specifically, majority of these candidates poorly target and infect human prostate cancers in vivo. More studies have been done with Adeno but problem is most humans have strong anti-adeno immune responses, especially antibodies, which can quickly eliminate it from the body before it can even infect tumor cells to be of any therapeutic use ( ). Decades of gene therapy data showed adeno virus is a poor candidate for human therapies because it drives strong immune responses against itself, This severely limits its therapeutic utility and yet this doesn’t seem to deter the flood of research resources, personnel and money flowing into such futile lines of enquiries. The oncolytic virus field seems prey to the same blinders. Bottom-line, at the moment, a prostate-specific oncolytic virus Rx is very much a work in progress rather than close to the clinic.
1. Liu, Ta-Chiang, Evanthia Galanis, and David Kirn. “Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.” Nature clinical practice Oncology 4.2 (2007): 101-117.
2. Pikor, Larissa A., John C. Bell, and Jean-Simon Diallo. “Oncolytic Viruses: Exploiting Cancer’s Deal with the Devil.” Trends in Cancer 1.4 (2015): 266-277.
3. Melcher, Alan, et al. “Thunder and lightning: immunotherapy and oncolytic viruses collide.” Molecular Therapy 19.6 (2011): 1008-1016.
4. Russell, Stephen J., Kah-Whye Peng, and John C. Bell. “Oncolytic virotherapy.” Nature biotechnology 30.7 (2012): 658-670.
5. A ‘huge milestone’: approval of cancer-hunting virus signals new treatment era. The Guardian, Nicky Woolf, November 2, 2015.
6. Kohlhapp, Frederick J., and Howard L. Kaufman. “Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy.” Clinical Cancer Research (2015): clincanres-2667
7. Andtbacka, Robert HI, et al. “Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.” Journal of Clinical Oncology 33.25 (2015): 2780-2788.
8. Ledford, H. “Cancer-fighting viruses win approval.” Nature 526.7575 (2015): 622-623.
9. Appleton, Elizabeth S., et al. “Talimogene laherparepvec in the treatment of melanoma.” Expert opinion on biological therapy 15.10 (2015): 1517-1530.
10. Harrington, Kevin J., et al. “Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1–derived oncolytic immunotherapy.” Expert review of anticancer therapy 15.12 (2015): 1389-1403.
11. Johnson, Douglas B., Igor Puzanov, and Mark C. Kelley. “Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.” Immunotherapy 7.6 (2015): 611-619.
12. Passer, Brent J., et al. “Combination of vinblastine and oncolytic herpes simplex virus vector expressing IL-12 therapy increases antitumor and antiangiogenic effects in prostate cancer models.” Cancer gene therapy 20.1 (2013): 17-24.
13. Elankumaran, Subbiah. “Genetically engineered Newcastle disease virus for prostate cancer: a magic bullet or a misfit.” Expert review of anticancer therapy 13.7 (2013): 769-772.
14. Chakrabarty, Romit, et al. “The oncolytic virus, pelareorep, as a novel anticancer agent: a review.” Investigational new drugs 33.3 (2015): 761-774.
15. Shulak, Laura, et al. “Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-κB-dependent autophagy.” Journal of virology 88.5 (2014): 2927-2940.
16. Nguyen, Tien V., et al. “Evaluation of polymer shielding for adenovirus serotype 6 (Ad6) for systemic virotherapy against human prostate cancers.” Molecular therapy oncolytics 3 (2016).