How malignant cells in patients with CLL escape T-cell recognition

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Published: 22 Jun 2012
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Dr Alan G Ramsay - Barts Cancer Institute, Queen Mary University of London, UK

Dr Ramsay talks to ecancer at EHA 2012 about how malignant cells in patients with Chronic Lymphocytic Leukaemia escape T-cell recognition and attack.

 

Dr Alan Ramsay presented findings of a study in patients with Chronic Lymphocytic Leukaemia that will contribute to the design of immunotherapeutic strategies leading to the killing of cancer cells.

 

T cell activation is essential for immunity including the recognition and killing of abnormal target cells such as cancerous cells.

 

T cell activity is tightly regulated by signaling at the contact site (referred to as the “immune synapse”) with a target cell.

 

These pre-clinical findings should help contribute to the design of immunotherapeutic strategies to specifically block these inhibitory molecules in cancer and to repair T cell recognition and killing of cancer cells.

 

Filming supported by Amgen

EHA 17

Impressive results with a bispecific antibody for ALL

Professor Max Topp – University of Wuerzberg, Germany


I’m delighted to have you with us, Max Topp from the University of Wuerzberg, isn’t it? You’ve been delivering a talk here on a bispecific monoclonal antibody, something called a T-cell engager. Now this is not just in the realms of science, it has actually done something with patients, hasn’t it? What did you do in this study?

We used this new antibody which is like a third generation antibody which recruits T-cells as its major effector cells to kill off the leukemic cells. So we’ve conducted now a phase II trial in patients with relapsed refractory BLL and asked the question can we put these patients in complete remission with two cycles of this new antibody construct as a single agent?

 

And what happened?

In 75% of the patients, so 26 out of 36 patients, actually reached a complete remission within two cycles of blinatumomab and, most importantly, the remission is not just a haematological remission but it’s also a very deep molecular remission so you have reduction of the leukemic burden by five logs.

 

Now unlike a drug like rituximab, for instance, which has one target basically, you’ve got two targets.

Correct.

 

Is that a more complete targeting of the immune system, is that why it works?

You actually have one target, it’s a C19 which is the target which is abundantly expressed on leukemic cells but C20, for example, isn’t expressed and about half of the leukaemia cells lack C20 expression. By actually having a bispecific antibody and using CD3 on the other site which can then recruit quite actively the T-cell to bring it very close to the leukaemia. So that is the new trick in getting the immune system engaged in killing off the leukaemia in that situation.

 

You’re getting complete remissions in two-thirds of the patients. Tell me a little bit more about that, it sounds quite good.

Well if you look at the historical control and ask the question what is the data out there with chemotherapy in this patient group, the best you can do is 35%. Even a patient who gets a complete remission, these patients will relapse ultimately most of the time. So currently, looking back at the historical control, the majority of papers have published that this patient cohort just lives four to six months. Within this study currently, with a median follow-up now of about nine months, median survival rate is at 10.7 months and that is the first results that we have on a time-sensitive endpoint. So it could well be that perhaps we can cure a couple of patients if we combine blinatumomab and then perform an allotransplant in this patient cohort.

 

And could you describe these patients a little bit more for me? You weren’t just lucky with these?

I think if we recruit 36 patients and they are really very bad prognosis patients, we had patients travelling all over the world to actually join this trial, even from Australia, to come to us to have actually the drug administered. So it really does present hope for patients in that situation and I think it is – those are quite remarkable, to achieve those kind of remissions in those patients.

 

And this is described as B precursor ALL.

Correct.

 

And that means exactly?

It is that the LL is… the origin of the malignant cell is a B-cell or a B-cell which is an early precursor of B-cell origin. So it doesn’t work on TLL because it lacks the C19 expression profile on those cells.

 

Now what’s the implication of the molecular remissions that you were also getting along with the haematological remissions?

Haematological remission is only just a reduction by one log of leukemic tumour burden. If the molecular remission means you have a reduction of about five logs so the tumour burden that you are dealing with is much lower and you have a better chance than, for example, using an allotransplant to actually cure the patient. Because, if you do a transplant in a patient with a very high molecular payload still, a lot of molecules being positive, this patient will relapse ultimately, even with an allotransplant. We’ve now performed an allotransplant in a couple of patients in those sequences and it looks like these patients are doing very well actually.

 

Do you regard, then, blinatumomab as a potential bridge to allotransplant?

Yes, definitely in the younger patient.

 

So what are your recommendations coming out of this to doctors? This is, of course, a very early stage, it’s not something people can apply right away.

Right, currently it is that we are conducting now another trial in five major European countries including England and in the United States. So a patient who has those kinds of features, so is relapsing, should potentially be referred to a study centre that is conducting this trial at the moment, potentially also giving this patient a chance. They’re recruiting very quickly, this trial. I think we can actually also go then, approach the legislators to get this drug approved for the treatment of leukaemia down the road. So that will be the intermediate step and in the future I really believe, because this drug is also remarkably non-toxic in comparison to chemotherapy, we only lost one patient out of 36, so a 3% treatment related mortality in comparison to standard therapy which you have a treatment related mortality of about 20% in this patient cohort. So you have also a cure, a huge reduction on toxicity, in this patient cohort so you could well imagine that this drug potentially can also move into front line chemotherapy of patients with ALL and including also paediatric cases.

 

You had some neurotoxicity, pyrexia, headaches and so on but these weren’t anything to worry about?

Well pyrexia and headaches is not really an issue. We had three patients who had a seizure and we don’t understand why patients get a seizure, there is no biomarker out there, it has nothing to do with age, anything like that. But what we do believe is that if we recognise a patient who gets a seizure, of course we stop the drug immediately, the patients recovers completely and can be replaced on the trial to receive blinatumomab again if the patient then gets an anti-seizure medication like capra, for example.

 

Now would you say then that targeting, using a bispecific agent to make T-cells become engaged, is the way forward? What should doctors, very briefly, take home from this?

I think it’s very exciting that if we can use antibodies which target tumour antigens or very tightly restricted antigens, I think the future will be that engaging different immune cells like T-cells, NKT cells, T-cells macrophages, it could well be that we are opening up a new avenue of tumour immunology that would really actually make a difference like Rituxan has done in the past.

 

Max it’s great to have you with us. Thank you very much for joining ecancer.tv.

Sure.