In its simplest form it arose as a solution for patients who post-transplant had developed these aggressive EBV lymphomas which is essentially a normal cell that has been infected by the EBV virus and starts growing out of control because your immune system isn’t there to control it.

The simplest form of adaptive cell therapy was really if you gave these patients T-cells from their donor you could eradicate the lymphoma.

What do the T-cells do? Do they fight the EBV or do they fight the lymphoma?

What they do is, like all T-cells, what they’re seeing is a combination of an HLA molecule on the cell surface, the self-molecule, with a piece of the EBV virus stuck in the groove of it.

So the T-cell sees that whole complex, HLA plus piece of EBV, and sees that as foreign and destroys the cell that has the EBV inside it.

In practical terms, what has this meant for patients undergoing transplant procedures?

That initial demonstration that T-cells, the bulk T-cells, could kill the lymphoma cells then led to the idea that if you could separate out the patients who got those bulk T-cells to kill the lymphoma cells, also some develop graft versus host disease, because there was no selection for the cells you wanted.

So then the idea was that you could culture out specifically the cells you wanted, the EBV specific T-cells, and give just them you could treat these lymphomas without inducing graft versus host disease.

How did you develop this into an off the shelf sort of medicine then?

Because it takes two months to make one of these lines, once a patient has the EBV lymphoma it’s too late to start making the line.

So the idea was we started making a line for patients who were at high risk of developing one of these lymphomas.

We do a lot of what’s called T-cell depleted transplants and those patients are at higher risk for developing these lymphomas.

So when a patient was coming in to the hospital for one of those transplants we would go to the donor, essentially in advance, and say, ‘Let’s start this line now.’ So those lines, especially the ones that were never used for the patient, are frozen and banked and available for off the shelf use.

In the off the shelf use do you use one line of T-cells or do you mix them together?

We use one at a time.

We have more than three hundred lines to choose from so we select them to match the patient in the ways that make the biggest difference in terms of treating the tumour but they’re not perfectly matched.

How do you do the matching?

They’re matched for at least two of eight HLA alleles, is what we refer to. So what would never be an appropriate match for stem cell donor but is enough for these T-cells.

The T-cells kill; the T-cells see that complex of HLA in a way that they are designed to see and we can demonstrate that before they’re even frozen we know how they’re seeing EBV.

This therapy has been given breakthrough status. Can you tell me what it has, in fact, achieved so far?

So far, and really the basis for that breakthrough status, is that for patients who get these lymphomas and do not have a complete response to rituximab or recur after getting rituximab, the median survival as looked at in a number of studies is only 16-56 days.

So it’s a very high risk, very rapidly progressive complication of transplant.

Of course rituximab is a possible treatment.

Yes, it is not an FDA approved treatment but it is typically the first line of treatment for these patients, yes.

So in this rituximab refractory group of patients we have responses of 63% and those are all durable responses.

Does this mean that this approach, using the T-cells, could become the first line therapy in this situation?

We’ve thought about that.

The issue with the idea of first line is simply that… well, it depends on how you’re referring to first line.

First line for prophylaxis is tricky for a third party product because it’s not durable.

We have not yet really looked at it in the first line setting.

Pretty much all the patients we’ve treated with the third party cells have been in the second line, in the rituximab failures.

What should doctors be thinking about this therapy now and how can it impact their work?

The most important thing right now is to think about as you’re giving the rituximab is the patient having an appropriate response which really, in most patients, should be a marked improvement by the time they’ve gotten a second dose of rituximab in this setting.

Could you walk me through the timeline? A patient receives a stem cell or bone marrow transplant, gets this relatively uncommon complication of the lympho-proliferative disorder. What happens and when should it happen? Because it has to happen quite quickly, doesn’t it?

It has to happen quite quickly.

Typically they’re picked up relatively quickly clinically.

Centres have different protocols for how they follow the viral load in the bloodstream but these patients who have true lymphomas typically present with fever and swollen lymph nodes and exudative pharyngitis or some symptoms.

They typically get rituximab, most centres are dosing on a weekly basis.

As I said, in most instances when patients have a complete response to rituximab you see the viral load drop even after the first dose of rituximab.

By somewhere 7-14 days into rituximab therapy you really should see a marked improvement in the clinical response.