EADO Congress 2015

HVEM expression in melanoma metastasis: prognosis correlation

Prof Daniel Olive - Marseilles Cancer Research Center, Marseilles, France

You’ve been looking at HVEM, now this is herpes virus entry mediator. This is a new player in melanoma, a new player to me, I suppose other people may have heard of it, but very interesting, a new way of looking at melanoma. What did you do in the study that you’ve just been presenting?

Basically, a first introduction before moving to this study. What we know for a while, more or less four or five years ago, we have preliminary work showing that unexpectedly you could find HVEM in some melanoma patients. That we didn’t understand at all at this time and what we observed is that melanoma cell lines from these patients were inhibiting the function of the T-cells within the lymph nodes of patients. So we were surprised and it led to the hypothesis that this might be a pathway inhibiting responses against the tumour.

So what did you do?

Basically it was to take tumour samples from the patients, to take as well the lymphocytes, and to demonstrate in vitro that you have inhibition of a function of the T-cell from the patient, autologous. So once this was done we continued the work until the level that is presented today, meaning that then we have done a retrospective study in patients with metastasis. The question asked was whether all the patients had the same expression level of HVEM, did they all express? Question one. The second: were there differences in the expression levels? And question three: is it related by any way to a prognosis for a patient in terms of overall survival of these patients. So, question one, we found that most of the patients, not all, most expressed HVEM but with a large array of expression levels. Some were really low and others were really bright. When we determined by pathology analysis the two subgroups of patients, certification with the ones that were bright and the others were low or negative, what was found is that in these patients with metastasis the ones that were having the higher expression behaved differently to the ones expressing lower.

So the HVEM expression level is related to the process of metastasis?

It’s correlated to survival. So it’s what we have found. We don’t know at this stage whether it’s a process which is appearing during the course of the disease, meaning that it’s mutations or epigenetic modifications that occur during the course of the disease and will lead to this expression, or is it something that is found throughout the life of a cancer.

So could it be a cause or an effect, effectively?

It’s impossible to say at this stage, of course.

Can you break this down a bit and explain why this might be involved in metastasis and progression of disease? It’s part of the TNF superfamily, isn’t it? What’s the significance of that?

Correct, so it belongs to the large family of TNF receptors and this one whose name you mentioned initially it was thought to be only the receptor for one of the proteins of herpes virus simplex one, that it is, of course, but what was found at the end is that this receptor is also a molecule involved in the function of the immune system, regulating most of the immune effects through what we call co-simulation. The second thing that we found is that it has various ligands, which is a molecule, and among them one is called BTLA present on most haematopoietic cells, including lymphocytes, and this interaction led to the inhibition of T-cell responses.

So BTLA is something that perhaps if you can inhibit it then you can get the T-cells back to do their job.

Correct. What we have in vitro but not presented in this study but was done in other studies we have done previously is that using antagonist antibodies, meaning antibodies that antagonise the interaction between HVEM and BTLA, restore the immune response at least ex vivo.

At this point can you say if HVEM can be used as a prognostic marker?

It’s a guess at this stage, based on this study, it’s 126 patients so it’s a good number but not sufficient to be totally sure. At this stage we need to increase the size of the cohort of patients tested and the goal is also, to answer your question regarding the natural history, to have patient series during the course of disease to answer your question whether it is something that is more related to the process of metastasis or independent of it in terms of the biology of the cancer.

Is it reasonable to start targeting it to find out whether there could be a therapeutic benefit?

There are some good premises and there are arguments to proceed this way so it’s basically what we intend to do. It’s among the targets that are looked at by different companies including ourselves.

So what should doctors take home from your findings on HVEM and its possible role in progression of melanoma?

It means that at this stage, thanks to the initial data on PD1/PD-L1 that we know was presented during this meeting, there are additional markers that are present in melanoma that are altering the immune response of patients, meaning that there are multiple ways, first, that will impair the response and that will permit to help development of the cancer. The second thing that might, based on your question, whether it’s something associated to some aggressiveness of the disease. In this case of course there is another implication because the first one would be to say that you have an impact on the immune system and the one would be to say that if this molecule is playing a role in the development of cancer it means that you have different strategies to look at by antibodies, targeted therapies, looking at the signalling of the TNF receptor, for instance. So there are different hypotheses and ways that we can move after.

Are there any things that doctors might do in their treatment now as a result of this emerging understanding?

I would say at this stage it’s important to have a series of patients that we can analyse to get these studies that have already reached information. I say this for people working in the hospitals but also pathologists working in the cities, pathologists, to have better co-ordination to get as much as possible the samples that can be analysed to have different biomarkers, as you mentioned previously, that we can look at and get better information for the follow-up in treating patients. If you have this it would permit you to test HVEM, for instance, the one would propose additional ones of course.