EBV lymphoproliferative disorders that you see following a marrow transplant or a cord blood transplant are these very rapidly aggressive tumours that are usually clonal B-cell lymphomas that emerge early after the transplant and largely reflect the fact that the transplant recipient is very, very heavily immunosuppressed.

So in a normal, unmodified marrow transplant they can be 1-3%, if you take the T-cells out of the graft it can be 5-7%, or if you have naïve T-cells, like a cord blood transplant, it’s about 3.5% of the cases can develop this.

What happens is you develop fever, usually with lymph nodes that are enlarged; you can have disease that affects, more often than not, the pharynx and they get sore throat or things but they have massive nodes, or they have them in the intestinal tract or even the brain.

The limitation is that they are very aggressive and untreated they have a very, very short lifespan, it has been measured as under a month.

What has been done for EBV lymphoproliferative disorder in the past?

In the past several years groups have used Rituxan, which is an antibody directed against B-cells.

About 50% of the patients will respond to that but those responses will be sustained in only about 50% of the individuals, that is for patients who have overt disease.

So what we had done back in 1995 is to show that you could use T-cells to deal with these, using T-cells derived from the transplant donor.

Our group, the Baylor group and other groups have done a lot of work using immunised T-cells grown in the test tube derived from the transplant donor to treat this.

As it has turned out, it takes very, very few cells to do it but they are able to induce durable remissions.

So that’s the new part.

What has been the problem in the past? Speed is an issue, isn’t it?

That’s right.

The making of the cells takes at least 60 days, more often it takes longer than that.

So what we’ve done is to develop a large bank of these cells, these are all ready for adoptive therapy, they’re all HLA typed so they’re ready to go.

We also have defined the HLA restriction of the T-cells. T-cells see a virus peptide in the context of an HLA molecule and because we’ve been able to identify this restriction we can pick cells that should be able to kill the patient’s tumour.

Can you tell me what you did in the study?

We studied a series of patients, 26 patients who received EBV specific T-cells from their transplant donor, and another 31 patients who received T-cells from a third party donor chosen from the bank.

We were looking, in the third party group in particular, at patients who had failed Rituxan. What we did was to give infusions of these T-cells once a week for three weeks.

We would wait then three weeks; we would potentially give a second cycle, depending upon their response.

What we found in the circumstance was that over 60% of the patients were able to receive a CR or very durable PR of the disease and in the third party cases in the first study, where we were using 1 million per kilogram dosing, it’s about 50% of these patients are doing perfectly well at a year and in the second study it’s 72%.

The important point there is these patients who do respond with a complete remission or a partial remission do not recur with EBV.

Basically you have an off the shelf agent to use.

That’s right.

So ultimately what we’re hoping, right now patients come to us to get this treatment but our ultimate hope would be that a centre that’s doing these kinds of analyses could send the HLA typing and the pathology and we could send cells back by return mail.

So what should cancer doctors think about all of this and what should they do for their patients? At the moment they just have to get in touch with you?

Correct, and if they do so we usually have a very rapid search system.

As I said, a very large proportion of individuals, 98.6% of the searches that we’ve requested we’ve been able to find a transplant appropriate T-cell for the treatment of these disorders.

If this is scaled up and this agent, this class of agent, becomes widely available, could you eliminate the threat of EBV lymphoproliferative disorder, do you think?

You potentially could.

Early on Dr Rooney at Baylor actually used these as a preventative, as a prophylaxis, and treated a large number of patients who never developed EBV.

The limitation you have with some of these viruses like EBV or CMV is you have to be sure that the T-cells that are infused see the virus.

So ultimately the issue will be treating patients who show evidence of the virus; at that time their T-cells can see the virus and they really do their job.

Prevention, clearly, for EBV is possible and for some of the other viruses it’s likely going to be very early therapy. It will eliminate a lot of the complications that we have.

What about the mutations happening within EBV, is that a threat?

It is an issue and one of the reasons why we think this bank is so useful.

Because EBV does have a tendency to have multiple mutations, there are multiple different strains of EBV, and in some instances those mutations affect the peptides that a T-cell would see.

What we’re able to do in this setting is to choose T-cells that are reactive against a different peptide presented by a different HLA and get around that.

We’ve found this to be effective in five of the first seven patients we’ve used this approach on.