Tumour specific immunotherapy in CLL

Prof Catherine Wu - Harvard Medical School, Boston, USA

Could you tell me a bit about your research into CLL?

The motivation for my work, which I think is the same motivation for most people in the CLL field, has been really trying to understand why some patients can go on for more than a decade with a sprinkling of therapy here and there and do rather well while others succumb to their disease within two years. Really, trying to get a handle on that clinical variability has really been a driving force for our search for trying to understand the disease better.

We are at a time of great excitement from the biology side because there are fantastic transformative new technologies that are really allowing us to crack open some of those mysteries. For more than five years now there has been the availability of next generation sequencing which allows us to take primary patient samples and go straight to those patient samples and try to understand at the level of DNA, RNA, what are those changes that are specific to the cancer and really begin to dissect out the variability between patients. Our initial work was focussed on a mere one hundred samples and by now we have looked at more than 500 cases. What has been quite striking is that with each leap in terms of the number of the cohort size we’ve really been able to, with greater sensitivity, understand what are the cancer genes that are driving this leukaemia. We’ve been able to uncover what are the pathways and even more so we’ve been able on an individual level to pick out the heterogeneity within individual samples. I think that’s a critical concept when you think about cancer and evolution and the selective pressures that are imposed by microenvironment in the therapy. In CLL this is especially relevant because we’re at the really revolutionary moment where now, more than ever, there are more therapeutic options that are available. And really trying to understand how these different therapies impose selective pressure is really important and also trying to understand what are the sources of resistance and relapse.

A seminal finding from the work that my group has been involved in is trying to use the mutational landscape as a way to dissect out the heterogeneity that’s present within individual cancers. What has become quite clear is that each individual with CLL, it’s not a uniform population but rather there is quite a diversity of sub-populations that can be identified on the basis of mutation. They are clonally related, molecular changes are acquired over time, but they are also the source or the fuel that is the source for evolution and that, in turn, are the seeds for resistance and relapse.

So that, in a nutshell, is what we’ve been working on. We’ve been using these sequencing approaches to try to dissect the evolutionary trajectories of each individual as they move through time and trying to understand what are those mutations that are relevant and important to be aware of in terms of relapse and response to therapy. We’re also quite interested in developing therapeutics that can address this heterogeneity and I just want to highlight that the role of immunity, from a therapeutic standpoint, will play an increasingly important role in the treatment of this disease.