In today’s society, cancer is no longer a foreign word. The chances that we know someone who has been diagnosed with or died from cancer are on the rise. In 2012 alone, the World Health Organisation (WHO) reported 32.6 million people living with cancer, 14.1 million new cases and 8.2 million deaths from cancer. Most fatalities result from late diagnosis or treatment. In many of these cases, the cancer cells have metastasised (or spread) to other organs and are beyond curability with current technologies. In cases of early detection, surgical procedures can be performed to remove the cancer, followed by chemotherapy and radiotherapy to kill any remaining “escaped” cells. These treatments have become so commonplace that they are considered obligatory for any cancer treatment regimen. Less recognised is that, after surgical excision and chemotherapy, 40-60% of cancers detected even in early stages of the disease would occur again, with a much higher rate of recurrence in late stage cancers. Recurrence arises from the “escape” of some cancer cells from surgery or chemotherapy which subsequently develop resistance towards chemotherapy drugs. And when they come back, they come back with a vengeance. These cancer cells continue to grow, forming a more aggressive cancerous cell population that current treatments cannot kill. Clearly, we need more effective anti-cancer therapies.

Progress in science and technology has made it possible to engineer viruses to kill cancer cells in patients. Viruses are very small particles, invisible even under a normal microscope. In order to replicate, viruses must infect specific cells in the host (such as plants, animals or bacteria). Infection occurs via proteins on the surface of the virus that act as a “key” that inserts into a “lock”, represented by receptor proteins on cell surface. The interaction between the two proteins helps the virus to enter the cell and begin to replicate. The key-and-lock system is so specific that viruses will only recognise specific cell types in the host. For example, hepatitis viruses infect liver cells but not brain cells. Similarly, a virus that infects cancer cells will not infect normal cells. Even if normal cells are infected by accident, defence proteins present in these cells, but not in their cancerous counterparts, will fight off the virus and prevent its replication.

Viruses kill cancer cells through a process known as “oncolysis” (“onco”: cancer; “lysis”: killing by disrupting the cell membrane). This phenomenon was first reported in the early 19th century in a cancer patient infected with the influenza virus. Curiously, the cancer shrank after infection with the virus. Although scientists did not fully understand the phenomenon, they suggested that the virus might have contributed to the remission. In the years that followed, substantial research focused on identifying existing viruses with similar cancer-killing properties. Surprisingly, many viruses were found to be very promising in destroying cancer cells. Some viruses, such as coxsackieviruses, reoviruses, herpes simplex viruses and adenoviruses, are responsible for the flu, cold sores, and gastrointestinal diseases in humans. Others, like Newcastle disease virus and vaccinia virus, are responsible for animal diseases. Whilst a number of viruses, including Newcastle disease virus and reoviruses, possess a natural ability to selectively kill cancer cells, others can be genetically modified to kill tumour cells but spare normal cells.

But how do viruses kill cancer cells? Generally, cancer cells were once normal cells with finite lifespans, dying through a process called programmed cell death. Cancer cells, however, may acquire mutations in genes responsible for cell death. This prevents cancer cells from undergoing normal programmed cell death and allows them to continue growing unchecked. This uncontrolled growth eventually leads to a lump of cancer cells and the creation of a favourable “habitat” for oncolytic viruses, which exploit the immortal properties of cancer cells as virus production factories. As the viruses mature, they burst open the cell and spread to surrounding cancer cells. In addition, as cancer cells are burst open and killed, the body’s immune cells are attracted to the “war zone” to clear the destroyed cells. This, in turn, educates our immune system to recognise distinct “traits” or cancer antigens, which act like a “cancer vaccine”, and start attacking remaining cancer cells including those at a distant site that display these antigens on their surface. As the cancer cell population is killed, the oncolytic viruses run out of host cells to grow in and are cleared by the body’s immune system.

Despite numerous studies indicating that oncolytic viruses are relatively safe for use in humans (see for example, [1]), the general public remains sceptical. Such scepticism is the very reason that therapeutic agents undergo many stages of preclinical trials on animals, followed by very closely monitored clinical trials in humans. Clinical trials commonly consist of three phases: phase I involves approximately 15-30 patients to determine the safe dosage, route of administration of the treatment and effects of the new treatment on the human body; phase II involves less than 100 patients to determine the effectiveness of the treatment for various cancers and also the treatment’s effect on human body; phase III involves hundreds to thousands of patients to compare the effectiveness of the new treatment compared to the current standard treatment. Many oncolytic viruses are currently in clinical trial phases I, II or III.  OncoVEX (herpes simplex virus) and Reolysin® (reovirus) are examples of oncolytic viruses currently being studied in phase III clinical trials. Once the therapeutic benefit has been demonstrated, they can be approved by the Food and Drug Administration (FDA) for use as cancer treatment in hospitals. In fact, 2015 was a historic year for cancer virotherapy. IMLYGIC™ (talimogene laherparepvec), a genetically modified herpes simplex virus, was the first oncolytic virus to be licenced by the FDA for the treatment of melanoma. In addition, Oncorine (adenovirus) has also been approved in China for use in cancer treatments.

So far, patients’ outcomes have been very promising, and clinical successes were reproducible [2,3]. Solid cancer masses in stage IV (final stage of cancer) patients have been shown to shrink or at least cease growing [4]. Importantly, these therapies may also give patients a better quality of life; virus treatments are associated with much fewer and milder side-effects (i.e. flu-like symptoms) compared to those from chemotherapy and radiotherapy [1,5]. Despite promising results in clinical trials, however, virotherapy does have its limitations. Though these viruses are used therapeutically, they are still recognised as foreign particles or “antigens” to our body. This alerts the body’s immune response to detect and eliminate the viruses from the body. In addition, the administration of viral therapies requires trained professionals and close monitoring of the patients during treatment. These requirements pose major obstacles and explain, at least in part, why only a few countries in the world currently provide this treatment. Nevertheless, with international teams of scientists currently working on genetically modifying oncolytic viruses to improve their safety and efficacy, and many more viruses under investigation with the hope of isolating more potent variants, the future is bright for virotherapy. One day, we hope to be able to treat cancer like a common flu or fever with widely available oncolytic virus pills and eliminate the public fear associated with cancer.

About the author:

Suet Lin Chia is a senior lecturer at the Department of Microbiology in the Faculty of Biotechnology and Biomolecular Sciences at the Universiti Putra Malaysia. He is currently a postdoctoral research fellow working on oncolytic virotherapy in the laboratory of Professor Len Seymour at the University of Oxford. The author has also collaborated extensively with Professor Datin Paduka Khatijah Yusoff in the field of virotherapy. Dr. Chia aims to contribute to the development of cancer therapeutics and welcomes collaborations with researchers with the same goal. The author can be contacted at suetlin@upm.edu.my. 

This article first appeared in the Scientific Malaysian Magazine Issue 12. Check out other articles in Issue 12 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 12 (PDF version)

References:

1. Zeh HJ, Downs-Canner S, McCart JA, Guo ZS, Rao UN, Ramalingam L, Thorne SH, Jones HL, Kalinski P, Wieckowski E, O’Malley ME, Daneshmand M, Hu K, Bell JC, Hwang TH, Moon A, Breitbach CJ, Kirn DH, Bartlett DL (2015) First-in-man study of Western Reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol Ther 23(1): 202–214.
2. Russell SJ, Peng KW, Bell JC (2012) Oncolytic virotherapy. Nat Biotechnol 30(7): 658–670.
3. Chiocca EA, Rabkin SD (2014) Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res 2(4): 295–300.
4. Carroll J (2013) Amgen trumpets T-Vec oncolytic virus results from Ph III melanoma study. Chicago, IL: FierceBiotech; 2013 [cited 2016 Feb 11]. 
5. Chen NG, Szalay AA (2011) Oncolytic virotherapy of Cancer in: Miner BR (ed.) Cancer management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures. Springer Science+Business Media B.V. pp.295-316.

Tarikh Input: 09/01/2018 | Kemaskini: 20/02/2019 | azah