Len Seymour, University of Oxford
As well as gene and cell therapy, one other approach being discussed here at Royal Holloway this week is virus therapy where the natural ability of viruses to infect cells can be hijacked for medical use including the treatment of cancer. Kate Lamble spoke to Dr. Len Seymour from Oxford University.
Len - Viral therapy provides some aspects of therapeutics that have not been possible before with regular chemotherapies. At one level, a very important level that allows for the therapeutic agent to amplify itself at the target site. And when I say that, I mean the virus itself will replicate selectively in cancer cells and produce very high numbers. So for example, one virus infecting a cell can go on to produce 10,000 maybe 50,000 copies of the virus inside the tumour cell which will then lyse the cell and spread to infect adjacent cells and repeat the process. So, you have the possibility to amplify the therapeutic actually within the target which is something that's never been possible with chemotherapeutic agents. With those agents, the highest concentrations of the drug are always present in the bloodstream on the way to the tumour. And therefore, they're confounded by significant off target side effects. So, bone marrow toxicities, or toxicities against hair follicles in the gut. Whereas with the virus, it really can be designed to have almost no off target toxicities.
Kate - When you're aiming for a virus to take a gene into the cancer cells, what are you aiming for it to do? Is it to kill the cells or just to stop it replicating?
Len - One of the main problems with cancer which we're increasingly understanding particularly since we've had whole genome sequencing of cancer cells, is that they contain a huge number of mutations.So, a typical colorectal or breast cancer cell carries something like 90 or 100 mutations.
So, to try to fix a cancer cell like that is a really difficult issue. So, it's very tempting to take the alternative approach which just say, "Well, let's not try to do it. Let's simply try to kill the cancer cells." So, we use viruses and their ability to kill cells by replicating and lysing cells, and you have also the possibility to express therapeutic proteins within the virus.
Although many of our agents are simply viruses that are killing the cells as they proliferate, we can encode additional proteins at the genetic level within the virus to mediate an intracellular biological effect or even having agents secreted from the infected tumour cells to affect other cells within the tumour that are not directly infected with the virus.
Kate - These cancer cells are genetically identical almost apart from these mutations to our own cells. How do we use that virus to tell those cancer cells apart from our normal cells?
Len - Many tumour cells seem to be selectively permissive for viruses, so they do have a level of intrinsic selectivity for wildtype viruses. But then on top of that, you can use genetic modification techniques to make viruses specifically exploit the tumour.
So, at one level, you can introduce tissue specific promoters which are selectively activated within the tumour cells to drive the virus. At another level, you can take components out of the virus and make it dependent on mutations that have occured in the tumour. There are many different approaches you can take to make viruses which depend on mutations.
Kate - Do we identify virus that's in the natural world and we think, "That's doing something good. We could use that in this certain way" or do we try and adapt them and we just pick a generic virus and adapt it to how we would use it with cancer?
Len - I think that's a great question because as a scientist, it's always tempting to go and look for really interesting clever virus that can do something sophisticated to a cell and which you can exploit. But it's also very important to keep your feet on the ground in terms of trying to translate something into the clinics and it's easier to translate something into the clinic, say, if there's a body of evidence about the virus already.
In the end, one of the most important things is the virus you're working with can be produced to launch quantities, you needed enormous amounts of material to be able then to take out for a clinical trial. Many viruses are difficult to manufacture in large quantities. So, in my mind, adenoviruses probably are the simplest and the best.
Kate - We find cancers all over the body in every different organ. Is virus therapy particularly effective over all of those different types of cancer or are some cancers more difficult to reach through this method?
Len - When people present with cancer, something like 80% of them go on to die from metastatic disease, which means the disease which is spread around the body. And so, for a therapy which is going to be effective, it must be able to be given systemically.
Now, viruses come into very difficult class of agents to give intravenously because the body has learned over a millenia to recognise them as pathogens. So somehow, we have to find a way to preserve the body or engineer the viruses where they can at least achieve access to disseminated tumours.
Now, there are several different ways you can do that. One way that has been looked at which is quite promising is to put a transient coating onto the virus to protect it during the delivery phase. Another possibility is to use a serotype of virus which has not been widely seen before and for which there are relatively small numbers of neutralising antibodies in the circulation. So, there are some tricks, but in the end, if a virus can be given intravenously to access disseminated cancer, then I think it's the only way you can use it to treat metastatic disease.
Kate - You're treating people with something that the body automatically reacts against. Can you harness the body's immune reaction at all?
Len - You touched on another really interesting point which is the immune situation of the tumour. Human tumours, by the time they present clinically have had normally several years to grow and adapt. So although tumours pick up an awful lot of mutations and you would think as they pick the mutations, they would become potentially immunogenic. The immunogenic variance have been weeded it out. So, the forms that survive in the cancer are the forms which are not that much immunogenic profile. So, although there are cancer antigens, they're not normally very strong antigens.
Now, on top of that, a tumour has become rather sophisticated in finding ways to evade immune detection. It can express a variety of different pathways that will allow it to suppress the local immune system. Now, this means that there can be a situation when a virus goes into a tumour and that the immune system has a level of suppresion already and this may be another reason why on a local level, a virus finds it a reasonable place for it to be proliferative.
But of course, the virus can express components within the tumour that can modulate some of these factors that regulate the immune status of the tumour. And so, where we dream of going is to make a virus that will, to some extent reverse the immune suppresion within the tumour and allow the body's immune system to recognise the tumour and create an anti-cancer vaccine.