Mankind has long suffered from virally-based diseases like rabies, polio, influenza, the common cold and in recent decades AIDS.
According to a fascinating review by Kelly & Russell (cited below, and which this blogger particularly commends to your attention as a read-me-first), the idea that at least some of those viruses sometimes could have unanticipated good side effects came from isolated case reports.
In these occasionally encountered notices from family doctors within medical journals, patients who had some well-diagnosed form of cancer, typically blood born, but also some solid tumors, and who subsequently caught influenza, the mumps, or the measles or some similar viral ailment, sometimes went into cancer remission.
A few brave experimentalists (with their equally brave or perhaps unwitting patients) sought to deliberately introduce live viruses in largely hopeless cancer cases with the hope that a similar “miracle” could be made to happen again.
The wild, untamed, viruses were introduced often via injections of crude extracts of human serum and tissues, or of infected lab animal parts, and in a few cases by pin-prick scratches such as were used for vaccinations.
Viruses tested included those associated with mumps, chickenpox, hepatitis, and even West Nile disease.
In terms of families of viral structures, there were adenoviruses, herpesviruses, paramyxoviruses, and picornaviruses, although the researchers at that time often could not precisely type the varieties, because their microscopes were often not powerful enough to determine precise structures. Nonetheless, serendipitously, this was a surprisingly representative sample of general viral types, that more modern researchers could eventually build upon.
Results were decidedly mixed. Not surprisingly, many of the patients showed quite a feverish immune reaction, with some acquiring the viral disease full-blown. Others had acute reactions at the injection site or in surrounding tissue, particularly in the nervous system, or developed encephalitis.
Many trials involved a number of patient deaths directly attributable to the treatment rather than the underlying cancer.
Nonetheless, a significant percentage (not usually a majority, but as much as a third in some clinical trials) showed remissions in their cancers. This often took the shape of solid tumors that began dying off through rotting internally, or in blood counts that returned to normal levels.
Given that virtually all of the patients would have otherwise soon died of their cancers, this was not a trivial outcome.
The problems were that most of the remissions were relatively brief (a matter of months) and starting in the 1950s, other cancer treatment approaches like radiation, chemotherapy and surgery were showing better and longer lasting results, making viral treatments seem relatively unpromising by comparison, and certainly riskier for the patient in many cases.
Progress in viral oncolysis was fitful, and was additionally frustrated by the fact that, time and again, many seemingly successful lab animal experiments yielded poor results when tried on humans.
One limiting factor was clear even in the 1950s: Using live human disease viruses, while effective in a good many patients at first, was ultimately self-limiting.
The patient fought the viral disease immunologically and the viruses intended for killing tumors, themselves got killed off before being able to finish their “oncolytic” job.
The strategy then shifted to viruses that attacked animals other than humans, to which humans were immune or to which they became only mildly ill. Under this scheme, the viruses could attack the tumors without themselves being wiped out by the body’s counterattack.
The first real winner in a wide search was the Newcastle virus. It wreaks havoc with poultry but most humans suffer mildly if at all. It continues to show good results in patients with certain types of melanoma.
The second winner in breaking down a small range of solid tumors was vesicular stomatitis virus. This pathogen primarily bothers only cattle, giving them mouth blisters, sometimes with involvement of dairy cow teats, and hooves. Later scientific analysis showed that it attacked only those human tumors with impaired interferon function.
Nonetheless, analyses like these showed that viruses selected or tailored for mildness towards humans, that were targeted towards specific tumor weaknesses, could, in fact, succeed.
A two-fold challenge emerged over the 1980s and 1990s: find out how to tailor viruses, and learn the hidden pitfalls of the life as a tumor. Genome sequencing and genetic engineering of viruses helped with this first effort, and the cell and tissue culture of tumors aided the second.
Today a number of viruses (most often mentioned are adenoviruses and vaccinia that are fundamentally less threatening ) have been built for battle with cancers. Their modes of action vary.
The most common approach is still the direct tumorlytic approach.
The injected virus preferentially invades the tumor, bypassing healthy tissue.
Virus particles penetrate tumor cell membranes, replicate themselves wildly, and generally cause the host cell to burst, releasing more virus particles to get into neighboring tumor cells, thereby repeating the cycle.
When viable tumor cells are depleted, the rather large number of viruses remaining hopefully gets filtered out harmlessly through the liver.
Another strategy is to inject the tumor with a virus and have that virus replicate, but not necessarily rupture all the tumor cells right away.
Rather, the increasing biochemical maintenance demands of this invading virus (typically called a suicide virus) makes the whole cell-virus complex susceptible to a follow-up injected drug, which might otherwise not kill either the cancer cell or the virus directly, but now clearly kills both.
The advantage of this approach is that such follow-up drugs are often not toxic to the healthy cells of the patient, since they require special activation by the peculiar biochemical condition of the host cell-virus complex, to do their cell killing. Once the destruction has occurred they are disarmed because they are once again without the biochemical triggers that make them actively toxic, and can circulate until filtered out by the liver.
A third strategy is to tailor the virus so that it anchors on the cancer cell surface and blocks some pore whose function is vital to the cell. The tumor cell eventually fades from disruption, often of its cell-cycle.
A newer variant of this are viruses engineered to anchor themselves firmly to the cancer cell membrane with one end of their structure, but which then grab with another end of their viral self onto the tail of the tumor cell’s own DNA strands. This keeps the cancer’s cell’s own replication machinery from participating in the cell cycle so no metastasis can occur.
Which cancers are being most actively researched with respect to viral oncolysis?
Most often mentioned are colon, prostate, and cervical. Less often, tumors of the breasts, and liver, as well as melanomas are reported as candidates for this new (but at the same time very old) approach.
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