Exciting Science: Oncolytic Viruses (Review published in PLOS Pathogens)

Science is awesome. But I expect you already knew that, dear readers o’mine. In science laboratories across the world, every day dedicated researchers are testing ideas, generating and evaluating hypotheses, critically analyzing observations, and thereby, making significant contribution to the humanity’s attempts to understand in greater depth and detail the wonderful natural world that surrounds us, of which we, along with other living beings and non-living objects, form a part.

Ho hum, you say? Not so fast, buster! During this very process, every so often an idea arises, brilliant in its conceptualization and fascinating in its potential to change the world and our understanding thereof. Not all such ideas admittedly survive the rigorous testing and pan out; but each such idea represents the progress of science and furtherance of knowledge, even if by a small amount, regardless of its success or failure.

In a recent issue of PLOS Pathogens, Canadian researchers Ilkow, Swift (Hey! That’s my Scilogs co-blogger and science communicator of the MMM Bite Size Science fame! *waves*), Bell and Diallo have authored a comprehensive review¹ titled: From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer; in this paper, they describe the current research findings around such a brilliant idea, an oncolytic virus. A virus with a natural propensity to selectively infecting tumor or cancerous cells and destroying them from within… Imagine that!

NOTE: In this narrative, I shall use tumor and cancer interchangably, although there is a subtle distinction; cancers are malignant entities, while a tumor – which indicates a solid or fluid-filled swelling of tissues – may be benign or malignant.

The idea captured my mind because of two main reasons: first, I am aware of the plausibility of such a biological therapy approach; all those countless hours spent reading science fiction and medical thrillers and avidly watching Sci-fi films had to have some positive effects! (That’s my story, and I am sticking to it, Mom!)

And secondly, within my close and extended families, there have recently been a couple of cancer-related situations, one of a metastasizing gastrointestinal tumor with virtually non-existent chance of recovery, and a death from hepatocellular carcinoma. And while coping with each such situation, I have had to console myself as well as the family members saying that an appropriate therapy that could have satisfactorily dealt with these cancers does not unfortunately exist yet. Yet. Oncolytic viruses can, in theory, potentially change that.

The simple elegance of the idea is astounding; allow me to explain in detail why I think so.

It is well recognized that there are genetic mutations that may render a previously-healthy, normal cell into a cancerous entity, a malignant cell that grows unchecked, divides uncontrollably to multiply its numbers, consumes nourishment, invades and destroys normal tissues – first nearby, and eventually at distal sites – and yet, does not die, continuing to live beyond the normal life span of the cell. Interestingly, during this progression from normal to cancer, certain hallmark changes appear in the biology of these cells, likely triggered by those same or related mutations. As Ilkow et al. describe in the review, these hallmarks include, among others:

• Resistance to cellular programming that causes each cell to die at the end of its natural lifetime (via a process called apoptosis).
• Ability to evade the normal immunological surveillance and defence mechanisms, employing various special tactics.
• Alterations in cellular metabolism that allow the provision of energy, super-charge the cellular synthetic mechanisms, and create an appropriate biochemical microenvironment — the final goal being facilitation of the unregulated cell division and proliferation.
• Ability to grow without the help of cellular factors that ordinarily trigger and promote the regulated growth of various cells.
• Most importantly, the ability to grow their own blood vessels (via a process called angiogenesis), thus ensuring a consistent flow of nutrients via blood to sustain the proliferating cancer cells.

Interestingly, these changes that confer a survival advantage upon the malignant tumor cells also extract a steep price in terms to making these cells more susceptible to certain viral infections. As mentioned in the review by Ilkow et al., the viruses able to infect the tumor cells belong to diverse families, including the viruses responsible for pox, measles, herpes, polio, viral diarrhea, various viral diseases afflicting cats and dogs, and so forth.

These viruses can gleefully shanghai the altered metabolic pathways already present in the tumor cells, and use them to their own advantage to establish themselves in the cell and replicate. Many of the cellular mechanisms that are effectively shut down in the tumor cells happen to be the same mechanisms that ordinarily protect a normal cell against viral infections – a key point in favor of the plausibility of targeted, therapeutic use of oncolytic viruses.

Some of these viruses are inherently drawn towards the conducive milieu provided by the tumor cells. Tumor cells are known to display an abundance of certain structures on their surfaces, which facilitate virus entry by allowing viruses to latch on to them; this interaction between tumor cells and the virus may be enhanced (and/or made more specific) via genetic reprogramming of the latter.

Some of the other viruses can be genetically modified in such a specific way that they cannot survive inside the body (or, in other words, they would remain inactive) until and unless these viruses ensconce themselves inside the tumor cells, where the mechanisms that drive and sustain the malignant cells would also complement vital viral functions.

Ilkow et al. describe the critical features of tumor cell growth that can be exploited by oncolytic viruses. For example, the viruses can:

• Use the extra amounts of nucleotides synthesized by the tumor cells for their own replication.
• Seize the protein synthesis system of the tumor cells to make viral proteins, including enzymes that assist viral propagation.
• Push the tumor cells to go on dividing frequently, so that the viruses can make use of the cellular biosynthetic machinery and mobilize necessary resources for their own survival and production of progeny.

But what would the viruses do once they are inside the tumor cells? This is a key question in determining the success of therapeutic oncolytic viruses. As the name suggests, the primary function of these viruses is to ‘lyse’ or destroy the tumor cells directly from within by using enzymes that break down the cell membranes. However, there are additional mechanisms by which these viruses aid the preferential killing of tumor cells, leaving normal cells aside. These include:

1. Production of a host of inflammatory and immunologically active molecules that incites the body’s innate and adaptive immune responses targeted against the tumor cells.
2. Partial virus-mediated internal damage of the tumor cells, which appears to lead to a more generalized anti-tumor immune response.
3. Genetic modification of the virus to re-initiate apoptosis in the tumor cells, either by overcoming the tumor-orchestrated block on apoptotic pathways, or by introducing gene segments that goad the tumor cells into committing suicide.
4. Combination/complementation of oncolytic virotherapy with immunotherapy (via various immune effector cells) and/or chemotherapy and radiotherapy.

Sounds phenomenally interesting, doesn’t it? It does to me. SO. MUCH. POTENTIAL. Of course, it is important to be circumspect about new therapeutic techniques, especially regarding the challenges to their success. We know that considerable heterogeneity exists not only amongst cancer patients themselves, but also – more importantly – amongst the tumor cells within a patient, leading to situations where oncolytic viruses do not find a suitable environment conducive to their intended function. Depending upon how the viruses are delivered (systemically, which is relatively easier to do, or directly into the tumor), the virus may encounter and be neutralized by the patient’s immune system before it has a chance to perform. An additional concern with using viruses is always to ensure that, prior to use, the virus itself is rendered incapable of causing disease beyond its activity inside tumor cells. But the good news is that refinement of ideas, iterative testing and optimization of the therapeutic system can go a long way to eliminate these challenges, as described in a comprehensive review by Russell et al. in Nature Biotechnology.

Lest I should get too excited and rambly, let me finish with a small list of therapeutic oncolytic viruses already being tried out; this list is abridged from the greatly informative Table 1 of Russell et al. linked above.

Review Paper Highlighted:

1. Carolina S. Ilkow, Stephanie L. Swift, John C. Bell, & Jean-Simon Diallo (2014). From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer PLOS Pathogen, 10 (1):e1003836; DOI: 10.1371/journal.ppat.1003836