It may seem unlikely that viruses could a key tool for fighting cancer. Viruses are known for causing human suffering and death – from the common cold to HIV and influenza. Because viruses are so good at invading and taking over cells they have great potential as cancer killers. The following section gives some background on cancer killing (oncolytic; onco=tumor lysis=breaking down) viruses and describes some of the most promising ones.
- History of Viruses as a Treatment for Cancer
- Viruses as Cancer Killers
- Herpes virus
- Measles virus
The idea of using viruses to treat cancer has been around a very long time.1 After it was observed that infection with viruses could lead to improvement (but not cure) of patients with leukemia, attempts were made to infect cancer patients with viruses to cure their cancers. While some responses were seen, the viral infections also caused illnesses and the death of some patients. Later trials, using viruses to treat cervical cancer, showed the ability of viruses to target cancer, but still did not extend the lives of the patients.
The first successes in virus cancer therapy were achieved in the 1970s using the mumps virus. Because mumps itself causes serious disease, use of an unaltered version of this virus was not a good idea. Since that time, many animal and human viruses have been investigated for their ability to kill cancer cells.
The path to approval of viruses for cancer was a long one! The first oncolytic virus to be approved was an adenovirus, approved in China (more below). 2
Despite the misery that viral infections cause to almost every kind of living thing, viruses themselves not considered to be alive. Unlike cells, viruses do not have biochemical processes like metabolism. Instead, viruses are parasites made of relatively simple protein and genetic parts. In order to survive and reproduce, viruses must take over control of living cells. In many cases, this process ends in the death of the infected cell.
To take over a cell, viruses first have to attach and enter cells through the cell surface. Cell membranes are dotted with many different proteins, which help the cell to stick to things, move, and complete other cellular activities. There are many types of proteins, each with a slightly different shape and function. Viruses also have proteins on their surfaces. The proteins on the virus bind to proteins on the surface of the target cell, like a key fitting into a lock. Once in place, the virus is able to enter the cell or inject its genetic material into the cell.
Once infected by a virus, a cell is forced to produce more viruses. Living cells have the ability to make copies of their genetic information and to reproduce. Viruses take advantage of this and force the cells to make copies of the virus’ genetic material instead of their own. Viruses also take over the machinery inside cells that produces proteins and other biological structures. Often the process ends in the release of many more viruses and the death of the infected cells.
But what if, instead of killing healthy cells, these viruses could be programmed to specifically target, infect, and kill cancer cells? Viruses can be used to fight cancer cells in two main ways: by infecting cancer cells and causing them to self-destruct (a process called apoptosis) or by triggering an immune response against the cancer cells.3 Cancers take root by evading the immune system, viral infections can alert the body that something is wrong.
The viruses used to treat cancer are changed so they can’t cause illness. During the process, scientists can insert genes that cause the virus to only target cancer cells (leaving all healthy cells unharmed) and/or disable the virus’ ability to take over healthy cells.4 Evidence shows that oncolytic viruses can destroy stubborn cancer-causing cells that are sometimes survive through current treatments.5 A handful of viruses are currently being investigated for use in cancer therapies; four of these - herpes simplex viruses, reovirus, measles virus and adenovirus - are described below:
Herpes is a common human infection generally spread to oral or genital areas through bodily fluids. Unaltered versions of herpes viruses can cause disease in humans (i.e. cold sores).
The herpes virus is easily genetically modified, making it a good tool for treating different types of cancer. Genes can be added to target cancer cells, improve delivery or increase the activity of chemotherapy.6 The viruses can be also coated and protected to increase the efficiency of the treatment.6 The presence of the herpes virus alters patient immune responses. Work is being done to see if this can cause immune cells to attack the cancer.7 8
In 2015 a herpes-based oncolytic virus (talimogene laherparepvec (T-VEC); brand name ImlygicTM ) became the first oncolytic virus approved by the U.S. Food and Drug Administration (FDA). T-VEC is approved for the treatment of some cases of melanoma skin cancer.9 10 11
Reoviruses are typically harmless. It is found in the gastrointestinal and respiratory tracts. Reovirus has potent abilities to shrink tumors.Tumors with mutations in the RAS oncogene are particularly susceptible to treatment with reovirus.12 A 2009 study showed that reoviruses can cause tumor regression in mice.13
Pelareorep (brand name Reolysin®) successfully completed a Phase II trial of patients with metastatic breast cancer.14 In the trial overall survival was significantly improved. A Phase III trial involving patients with head and neck cancers is currently ongoing.15 Other clinical trials of pelareorep are onging.
Measles virus causes an infectious disease of the same name. The virus frequently attacks the respiratory tract of young children. Researchers have used the measles virus to develop MV-NIS, a virus which targets a protein (called CD46) found on most myeloma cells.16 CD46 provides a doorway into the cell for MV-NIS. A 2014 study showed that MV-NIS appeared to reduce tumor size in two patients.17 Clinical trials with MV-NIS are underway.
Adenovirus is different from the others on this list because it can target resting (nondividing) cells in addition to dividing cells. It can cause mild upper-respiratory or digestive infections in healthy humans.18 The adenoviruses used for cancer are genetically altered. The altered viruses are called recombinant conditionally replicative adenoviruses (CRAds).They have been changed so they can only reproduce in cancer cells, not in healthy cells.19 Wild-type (not genetically modified) adenoviruses attach to normal cells by binding to a protein on the surface of the cells. the receptor protein is found on many healthy cells, but very few tumor cells.20 First, scientists genetically modify the viruses so that the viruses are unable to attach to this receptor and therefore unable to infect healthy cells. The viruses can be also engineered to carry a variety of genes used to help the viruses accurately identify, infect, and destroy tumor cells.21 Some studies have shown that when used in with chemotherapy, CRAds can improve patient outcomes.22
In November 2005, an oncolytic adenovirus (H101) became the first one to be approved for use in people. H101 was approved in China for the treatment of some patients with head and neck cancers.2
For over 12,000 years poxviruses caused illness and death. Smallpox is thought to have killed hundreds of millions of people.23
Smallpox was also the driving force for the creation of the first vaccine. Based on work previously done by others, Edward Jenner, an English physician intentionally infected a young man with cowpox and then with smallpox. He was protected! The results paved the way for the development of an effective vaccines against several different viral infections. The horror of smallpox was ended in 1979 after a massive global immunization program eliminated the disease.24 25
In the last few years, modified poxviruses have gained attention for their ability to kill cancer cells and induce a strong immune response against tumors.26
- 1Kelly E, Russell SJ. History of oncolytic viruses: genesis to genetic engineering. Mol Ther. 2007 Apr;15(4):651-9. Epub 2007 Feb 13. [PUBMED]
- 2 a b Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006 Mar 1;98(5):298-300. [PUBMED]
- 3Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy.Cancer Immunol Res. 2014 Apr;2(4):295-300. [PUBMED]
- 4Timothy P Cripe, Pin-Yi Wang, Paola Marcato, Yonatan Mahller and Patrick Lee. Targeting Cancer-initiating Cells With Oncolytic Viruses. Mol Ther. 2009 Oct; 17(10): 1677–1682. [PUBMED]
- 5Yonatan Y. Mahller Jon Williams, William Baird, Bryan Mitton, Jonathan Grossheim, Yoshinaga Saeki, Jose Cancelas, Nancy Ratner and Timothy Cripe. Neuroblastoma Cell Lines Contain Pluripotent Tumor Initiating Cells That Are Susceptible to a Targeted Oncolytic Virus. PLoS One. 2009; 4(1): e4235. Published online 2009 Jan 21. doi: 10.1371/journal.pone.0004235 [PUBMED]
- 6 a b Duebgen M1, Martinez-Quintanilla J1, Tamura K1, Hingtgen S, Redjal N, Wakimoto H, Shah K. Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J Natl Cancer Inst. 2014 May 16;106(6):dju090. doi: 10.1093/jnci/dju090. [PUBMED]
- 7Yin J, Markert JM, Leavenworth JW. Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy. Front Oncol. 2017 Jun 26;7:136. doi: 10.3389/fonc.2017.00136. eCollection 2017. [PUBMED]
- 8Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014 Apr;2(4):295-300. doi: 10.1158/2326-6066.CIR-14-0015. [PUBMED]
- 9Imlygic Information from the FDA. Accessed 8-1-2018 [LINK]
- 10Ledford H. Cancer-fighting viruses win approval. Nature. 2015 Oct 29;526(7575):622-3. doi: 10.1038/526622a. [PUBMED]
- 11T-VEC Manufacturer's Website Accessed 8-1-2018 [LINK]
- 12 Gong J, Mita MM. Activated ras signaling pathways and reovirus oncolysis: an update on the mechanism of preferential reovirus replication in cancer cells. Front Oncol. 2014 Jun 26;4:167. doi: 10.3389/fonc.2014.00167. eCollection 2014. [PUBMED]
- 13Paola Marcato, Cheryl A Dean, Carman A Giacomantonio, and Patrick WK Lee. Oncolytic Reovirus Effectively Targets Breast Cancer Stem Cells Mol Ther. 2009 Jun; 17(6): 972–979. doi: 10.1038/mt.2009.58 [PUBMED]
- 14Bernstein V, Ellard SL, Dent SF, Tu D, Mates M, Dhesy-Thind SK, Panasci L, Gelmon KA, Salim M, Song X, Clemons M, Ksienski D, Verma S, Simmons C, Lui H, Chi K, Feilotter H, Hagerman LJ, Seymour L. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213. Breast Cancer Res Treat. 2018 Jan;167(2):485-493. doi: 10.1007/s10549-017-4538-4. [PUBMED]
- 15Clinical Trials Information for Efficacy Study of REOLYSIN® in Combination With Paclitaxel and Carboplatin in Platinum-Refractory Head and Neck Cancers. Accessed 8-1-2018 [LINK]
- 16Dingli D, Peng KW, Harvey ME, et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood. 2004;103(5):1641–1646. [PUBMED]
- 17Stephen J. Russell, MD, PhD, Mark J. Federspiel, PhD, Kah-Whye Peng, PhD, Caili Tong, MS, David Dingli, MD, PhD, William G. Morice, MD, PhD, Val Lowe, MD, Michael K. O’Connor, PhD, Robert A. Kyle, MD, Nelson Leung, MD, Francis K. Buadi, MD, S. Vincent Rajkumar, MD, Morie A. Gertz, MD, Martha Q. Lacy, MD, and Angela Dispenzieri, MD. Remission of Disseminated Cancer After Systemic Oncolytic Virotherapy Mayo Clin Proc. 2014 Jul; 89(7): 926–933. doi: 10.1016/j.mayocp.2014.04.003 [PUBMED]
- 18Lynch JP 3rd, Fishbein M, Echavarria M. Adenovirus. Semin Respir Crit Care Med. 2011 Aug;32(4):494-511. doi: 10.1055/s-0031-1283287. [PUBMED]
- 19Oosterhoff D, van Beusechem VW. Conditionally replicating adenoviruses as anticancer agents and ways to improve their efficacy. J Exp Ther Oncol. 2004 Apr;4(1):37-57. [PUBMED]
- 20Timothy P Cripe, Pin-Yi Wang, Paola Marcato, Yonatan Y Mahller, and Patrick WK Lee. Targeting Cancer-initiating Cells With Oncolytic Viruses Mol Ther. 2009 Oct; 17(10): 1677–1682. Published online 2009 Aug 11. doi: 10.1038/mt.2009.193 [PUBMED]
- 21Sherry W. Yang, James J. Cody, Angel A. Rivera, Reinhard Waehler, Minghui Wang, Kristopher J. Kimball, Ronald A. Alvarez, Gene P. Siegal, Joanne T. Douglas, and Selvarangan Ponnazhag. Conditionally-Replicating Adenovirus Expressing TIMP2 for Ovarian Cancer Therapy Clin Cancer Res. 2011 Feb 1; 17(3) doi: 10.1158/1078-0432.CCR-10-1628. [PUBMED]
- 22C K Ingemarsdotter, S K Baird, C M Connell, D Öberg, G Halldén, and I A McNeish. Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer Oncogene. 2010 Nov 11; 29(45): 6051–6063. doi: 10.1038/onc.2010.335 [PUBMED]
- 23Simmons BJ, Falto-Aizpurua LA, Griffith RD, Nouri K. Smallpox: 12,000 years from plagues to eradication: a dermatologic ailment shaping the face of society. JAMA Dermatol. 2015 May;151(5):521. doi: 10.1001/jamadermatol.2014.4812. [PUBMED]
- 24Thèves C, Crubézy E, Biagini P.History of Smallpox and Its Spread in Human Populations. Microbiol Spectr. 2016 Aug;4(4). doi: 10.1128/microbiolspec.PoH-0004-2014. [PUBMED]
- 25Stewart AJ, Devlin PM. The history of the smallpox vaccine. J Infect. 2006;52(5):329–334. doi:10.1016/j.jinf.2005.07.021 [PUBMED]
- 26Ricordel M, Foloppe J, Pichon C, et al. Cowpox Virus: A New and Armed Oncolytic Poxvirus. Mol Ther Oncolytics. 2017;7:1–11. Published 2017 Aug 24. doi:10.1016/j.omto.2017.08.003 [PUBMED]