Treatment of acute lymphoblastic leukaemia by activation of patient's immune cells by a bispecific antibody

Share :
Published: 20 Jun 2014
Views: 2988
Rating:
Save
Dr Nicola Gökbuget - Goethe University Frankfurt, Frankfurt, Germany

Dr Gökbuget talks to ecancertv at EHA 2014 about the use of antibody treatments in acute lymphoblastic leukaemia.

Read the article for more.

 

This is a combination of two targets; it’s a very small molecule which has in one part a CD3 and this CD3 part attracts T-cells which are in the body, so the normal immune system. On the other side is the bispecific antibody, this has a CD19 part and this CD19 attaches to the target cell. The target cell is the leukaemia cell which has CD19 on the surface. So the bispecific antibody brings the T-cells very close to the target cell and this activates, actually, the T-cell and the T-cell proliferates and kills the target cell.

T-cells are designed to kill but may not be doing so in their leukemic setting?

No, because they don’t identify the target cells but by the bispecific antibody they are brought directly to the target cell and then they can even detach after killing one cell and then seek for the next target cell and kill it. So it’s a serial kill, very effective, where a very small concentration of the molecule can kill a large amount of leukaemia cells.

So that means limiting the toxicity to the rest of the patient?

The toxicity depends also on the activation of the T-cells, of course, because they release cytokines, for example, and this contributes to the toxicity as part of this treatment.

What category of patients were you treating?

These were patients with relapse of refractory disease. This means they had first a response to the chemotherapy and then relapsed. We selected specifically a poor subgroup, meaning patients with early relapse, within twelve months of first remission. This was one major group then refractory relapses, patients who had a salvage treatment and didn’t respond, relapsed after stem cell transplantation which is also a very unfavourable group and patients with primary refractory disease, these are patients who never responded to any standard therapy.

What are the chances of severe risk patients responding to more chemotherapy?

They usually get again a combination chemotherapy and the response rate for these types of patients is around 30%.

What happened when you gave these patients blinatumomab?

The response rate was overall with this approach 43% complete remissions and this is quite a good proportion in such an unfavourable patient population. In addition, not only the complete remission measured by microscopy was seen but in these CR patients 80% had a molecular remission, meaning that they had less than 0.01% blast cells in the bone marrow.

You say this has a considerable anti-tumour effect and has increased CR rate. What should doctors make of this?

First of all such trials have the aim to show that a new compound has an anti-leukemic efficacy so this has to be shown also for registration purposes of the drug of course. Then if the patient has a CR the patient has a chance to get a stem cell transplantation and this is a major method to achieve a cure in these patients. So they have a CR with this new compound and then get a transplant and then the patient has a chance to be cured. This is, for the moment, the situation which we can do with this drug. In the future, of course, there are other options.

Of your 189 patients, how many have had access to a potential cure that may not have had before?

It depends all on the CR rate so the CR offers a chance to have the transplant. So since we had for the 3% CR it is a higher chance to get a transplant than with the standard therapy but there are many other factors confounding, of course, the chance of a transplantation so it’s difficult to make a guess because the transplantation depends on whether they have a donor or whether the healthcare system pays for transplant so there are many factors. It’s not an issue of the drug, it’s more a general issue. So the drug gives you the opportunity to just offer the patient the transplantation.

Are these results good enough to move into phase III and potentially register this as an agent?

Absolutely. This is a single drug and I think the result is very good. If you look for history, other drugs registered for ALL like nelarabine or clofarabine, they have single drug activity of 20% CR rate so we have to keep in mind this is a poor population and I think absolutely that we can use this drug at the better situations, even in the future, for example, in low level disease like minimal residual disease status or even in the first line treatment.

What are the overall clinical implications coming from your study?

First of all we know now that this drug is effective and we have learned a lot also about tolerability. It gives an opportunity to integrate this compound which has a totally different mechanism of action compared to chemotherapy in the future first line management of ALL. This is the big hope that we have, not only chemotherapy but different approaches to treat these patients. For example, to reduce the number of resistant developments in these patients.

What are the toxicities that you might find?

Mainly the major toxicities are related to the cytokines, like fever is a typical sign or headache. The patients also show a drop in peripheral blood count; they show an increase of CRP for example, so all signs of inflammatory signs which are related to cytokines. There’s another type of toxicity which is cerebral toxicity, CNS toxicity like encephalopathy or seizures that can occur also in part of the patients; it has been observed in the past for other T-cell based therapies.

How would you sum up your findings?

The important thing here is that we have really proof of principle in a very large number of patients that the T-cell targeted therapy can be effective in a very aggressive subset of acute leukaemia. This is a very interesting result and hopefully can be expanded in the future also to other disease entities and to other situations in ALL patients.