ASH 2014

Children with aggressive leukaemia experiencing remission with T cell therapy

Dr Stephan Grupp - The Children's Hospital of Philadelphia, Philadelphia, USA

Unfortunately what was special about these kids is that their standard treatments hadn’t worked; chemotherapy wasn’t working for these kids. Actually two-thirds of the patients that we’ve treated had already had a bone marrow transplant and that hadn’t worked for them. So these are really unfortunately patients with almost no treatment options at all when they come to us.

Can you run me through what the CAR T-cell therapy is? It’s individualised, isn’t it? So what do you actually have to do with each patient?

That’s correct. So, in order to do this we actually have to get T-cells, which are the feedstock of the CAR manufacturing process, from each patient, so that’s a one patient, one lot, one infusion approach which is, of course, somewhat complicated. We collect the T-cells from the kids, they undergo a manufacturing process that genetically modifies the T-cells. Those genetically modified T-cells are grown up over about a three week period and then they’re available to give back to the kids.

And when they’re given back to the kids they do what?

The actual process of giving them back is just a quick intravenous infusion but then what the cells do that’s important is that they grow. So they go into the patient and they grow and grow and grow in response to the leukaemia that they see. I think that that’s the key to how these cells work.

So they’re helping the child’s natural ability to fight those leukaemic cells, is that it?

They’re harnessing the potential ability of the immune system to fight the cells but the trouble is the T-cells can’t see cancer. These modified T-cells can see the cancer and then they grow like T-cells do and they kill cancer like T-cells can and as long as there is leukaemia they hunt it out wherever it is. So the ability of the T-cells to grow is the key thing.

And there’s no immunological backlash of graft versus host?

There is an immunological backlash but it’s different. So there is no graft versus host, even in patients who had a transplant where the T-cells that we collect from them were ultimately derived from their donor. We’ve seen zero graft versus host disease so I think that’s very important. But there is something called cytokine release syndrome and cytokine release syndrome is an immune hyper-activation syndrome that we see in patients with very high disease burdens and some of those patients, about a third of those patients, can get pretty sick.

Now you’ve been using it in 39 children which in CAR T-cell therapy terms is a massive large study.

This is a very large study, yes.

What did you do?

39 kids came to us for CAR T-cell treatment, either relapsed after transplant or with refractory disease, and those patients got their T-cells and after a month we assessed all of them. 36 of them were in a complete response, so 92%.

And was that your primary objective in this case?

The primary objective is absolutely can we get these kids into remission but the key thing in the data that we have now is that we followed some of these kids for a longer period of time, so the median follow-up is six months. The likelihood that a patient remains in remission at six months if they went into remission is 76%, most of whom did not get any further treatment like, for instance, stem cell transplant. So that’s very important, I think.

What about survival and what about cure?

Cure is hard to define, you have to define a time where you think the patients might be cured. We don’t know the answer to that but we have patients who are a year out and even as far as two and a half years out that have remained in remission without further treatment. So we can talk about longer term disease control in those kids.

Clearly a therapy like this that’s individualised is not that easy to implement everywhere. What are the clinical implications for ordinary doctors right now?

The first step is that this has been licensed by a drug company, Novartis, they’re going to have to figure out how to make these products for hospitals across the country. There is already a paediatric multi-site trial where they’re going to figure this all out so this is going to happen in the next year, which I think is very exciting. The next thing is that since some of these patients have cytokine release syndrome we have to train the doctors in how to manage that. So we’re in the midst of doing that as well.

So what’s the take home message for doctors then?

I think the take home message for doctors is that this is a very powerful therapy for the group of patients where other therapies, especially conventional chemo and transplant hasn’t worked and that in the future this may actually be something that might replace bone marrow transplant.

And the bottom line on what you’ve achieved?

The bottom line is 92% complete response rate, two-thirds of whom have remained in remission for up to six months and even longer.