Thursday 24 November 2011

Arginine, Glioblastoma and the Immune System

An interesting piece of work came to my attention earlier this week that I think is worth sharing for a number of reasons. Firstly, I think it illustrates a way of working that really should be encouraged - it has significance beyond the specific interventions mentioned. Secondly, I think there are lessons here for those who are interested in anti-cancer agents not patented by the drug companies (such as curcumin, quercetin, resveratrol etc). Finally, it has interest for those suffering from glioblastoma (GBM) - a form of brain cancer that is particularly aggressive and hard to treat.

The work in question looked specifically at the phenomenon of immune suppression in GBM patients, and let's note at the outset that immune suppression is a problem for all cancer patients, not just those with GBM. Brain cancer patients - not just those with GBM - at the University of Colorado Hospital had blood taken and analysed, along with blood from non-cancer patients. Analysis revealed that the blood from GBM patients in particular showed lower levels of T-cell proliferation and released lower levels of interferon-gamma compared to normal blood samples - in other words they had lower levels of immune function. The specific forms of this immune suppression were worked out in a series of lab experiments that ultimately showed that one of the factors associated with this suppression was a high level of the enzyme Arginase I (ArgI). This enzyme consumes the amino acid Arginine, which is essential for T-cell activation.

So far so good - it's interesting, in an academic way, but so what? The experimenters then took the next step and looked at chemically blocking ArgI with a specific drug. Doing this improved the immune response in the test tube. Levels of interferon-gamma rose to normal levels. The next step, however, is where it gets really interesting from a patient point of view. Rather than blocking ArgI with a drug, the team looked at increasing levels of Arginine (which is what ArgI consumes). By adding more Arginine the immune response improved. In simple terms the ArgI was basically using up the circulating Arginine and thus starving the T-cells of it, but by increasing the amount of Arginine the researchers showed that they could 'feed' the ArgI and have enough left over to be used by the T-cells, which could become activated as normal.
Arginine is an amino acid that is commonly available as a supplement, it's cheap and easy to take. It has also been used clinically in patients for improving immune function in patients suffering major trauma or undergoing major surgery. There is evidence therefore, that it's safe to take, and that it can improve immune function in these patients.

The authors of this paper have started a small clinical trial with GBM patients to see if oral supplementation with Arginine can restore immune function. It's an open question as to what effect restoration of immunity will have in terms of tumour growth, but at the very least it may be a useful aid to any immunotherapy treatments that may become available.

Now, aside from this being good news for GBM patients, I think this piece of work has some good things to teach us.

First, this form of work - from initial clinical investigation, to a series of laboratory experiments, to a specific hypothesis tested in a test tube and then, based on these results, to a small clinical trial - is just what we want to see more of. Instead of spending countless years in the lab before even getting to think about clinical benefits, this team have moved very quickly. I call this from form of cancer research the 'bench to bedside' model, and we need to see much more of it.

Secondly, the authors could have carried on looking at patented drugs that blocked the action of ArgI, but they looked also at a natural substance, the amino acid Arginine. This isn't owned by anyone, it's cheap and it's safe. When they got good results in the lab, they checked that there was prior evidence of safety and clinical use and then moved to kicking off a small clinical trial. That's how it should be done. Too often we hear that it takes millions to get a treatment to the trial phase. It doesn't have to be like that. And it certainly doesn't need to have a big drug company behind it either. If the trial fails then it can still provide useful information for future work. If it does work and can provide clinical benefit then things can go forward to larger scale randomised controlled trials.

Finally, immune suppression is a generic problem in cancer. ArgI might not be an issue in all cancers, but if it is discovered that it is, then this work has much wider implications. Furthermore, immune suppression is a problem with immunotherapies, so a way to overcome it at the same time as immunotherapy treatment would be a great strategy to explore.

For all these reasons, I think the team of Trisha R. Sippel, Jason White, Kamalika Nag, Vadim Tsvankin, Marci Klaassen, B.K. Kleinschmidt-DeMasters and Allen Waziri deserve our thanks and encouragement.

For those who want to follow up on this, the paper is available on open access (i.e. free - yet another reason to like this work!) from the journal Clinical Cancer Research here:

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