Human B-cell receptor structure and function in CLL

Prof Freda Stevenson - University of Southampton, Southampton, UK

We described in 1999 that CLL, far from being a single disease, is actually two diseases and this was based on looking at the genetics of the immunoglobulin molecule which is on the cell surface of CLL cells. If you look at this, one of these subsets has unmutated genes, and this is a natural mutation not a cancer-inducing mutation. So one subset has unmutated genes, the other has mutated genes. What it tells you is that the cell of origin of these two subsets of CLL is different. That may seem a little academic but in fact it turns out to be really important because those with unmutated genes, immunoglobulin genes, have a much worse prognosis. So it has separated the two into very dramatically different subsets.

So that was the first observation and now in the clinical trials and for patients in general the gene sequences are being looked at to see if the patient is assigned to the good or the bad prognosis group. But perhaps more importantly the surface immunoglobulin which we were studying turns out to be a target for therapy. The cells are driven through that by antigens in the body and this is important in terms of the progression of the disease. It turns out that the unmutated subset is more open to being driven so it proliferates more and that’s probably the reason for the progressive disease in that subset.

In terms of targeting there are several drugs now being used. Perhaps the most advanced one is so-called ibrutinib which inhibits one of the molecules involved in signalling through the surface immunoglobulin; it’s called Bruton’s tyrosine kinase, BTK. So this BTK signals the cell from the immunoglobulin receptor to the nucleus and the drugs have been specifically designed to inhibit that target molecule, the BTK molecule. For the first time, we’re finding patients respond dramatically to this drug and the most dramatic response is in the unmutated, bad prognosis subset. Whereas the better prognosis subset probably doesn’t respond quite as well but that may not matter quite so much because it’s got a better prognosis.

So there’s a whole raft of drugs coming on, following the ibrutinib, targeting various molecules in this signalling pathway. What they do can be explained by the clinicians but, just very briefly, the disease sits in the lymph nodes so you can get swollen lymph nodes, a swollen spleen etc. and when you take the drug because you’ve got CLL the cancer cells are mobilised from the tissue into the blood and there they’re not as happy to survive so they gradually die off. So you get initial lymphocytosis, an increase in white cell count, as the tumour cells drain from the sites and then they gradually die away due to the cytotoxic effects of the drug. The patients are doing remarkably well by three or four different kinds of drugs targeting three or four molecules involved in this pathway.

So it all looks very positive but of course there’s more to do. What we’ve been looking at is looking a bit further down the pathway to try and look at molecules that might be also targetable without side effects. There are some side effects with the current raft of drugs, not too bad but some of them are, so we’re looking at different pathways to target, particularly the MEK pathway which is activated in a number of cancers and for which there are small molecule drugs being developed.

So the next steps in your research, exactly what are you doing right now?

Well what we’re doing now is looking at MEK, we’re looking at the effects within the cells of changes in RNA translation. So we’re getting closer to the proteins that are being made in the cancer cell and trying to target the mechanism by which these proteins are made. So this is downstream of the signalling pathways targeting some of the proteins which should be more specific and should have fewer side effects hopefully. But this is a whole new area of research but it overlaps with other cancers as well as this one.