EHA 2016

Cured AML patients generate anti-tumour antibodies that kill AML blasts

Dr Mette Hazenberg - Academic Medical Center, Amsterdam, The Netherlands

Most of the research that I’ve been presenting here is about antibodies that are directed against acute myeloid leukaemia. These antibodies we found by searching the B-cell repertoire of patients that cleared their leukaemia after allogeneic stem cell transplantation. What is very exciting and interesting about our research is that we did not decide what the target of immunotherapy is but we investigated what the immune system decided what the target of anti-tumour responses should be and that’s exactly what we did.

Can you tell us more about how this research was conducted?

What we did was we selected a few patients that had high risk leukaemia, relapsed leukaemia, for example, after transplantation that nevertheless after, for example, donor lymphocyte infusion or after a second transplant cleared their leukaemia. We isolated their B-cells and we immortalised these B-cells by transfusing them with Bcl-6 and Bcl-xL and by doing so these B-cells are arrested in a state where they express the B-cell receptor on their surface and they produce antibodies but they don’t differentiate any further. So you can do this and you can keep these cells in cultures for a long time. They produce antibodies that you then can use for investigation so what we did was we used a supernatant of these B-cell cultures that contains the antibodies and screened that supernatant for binding to target cells of interest, so leukemic cell lines basically but also blasts from patients. By doing that we found quite a number, from three patients we actually found seventeen B-cell clones that are specifically directed against leukaemia AML but did not bind to all sorts of healthy tissues.

So you’ve managed to take… I suppose it would be the graft anti-leukaemia reaction?

Exactly.

And direct that in a more anti-tumour fashion.

Exactly, that’s what we did.

Would these kinds of B-cells be maybe a transferable course for therapy if people have this innate reaction to this?

Yes, I think they would because these are human antibodies. The technology that we used was developed by a spin-off company of the Academic Medical Centre in Amsterdam and the company is called AIMM Therapeutics. By doing the same thing they also made very interesting anti-RS virus antibodies that are actually now already tested in humans. From these studies we know that these human antibodies are safe and can be used for therapy or prevention in other human beings.

Is that something that you would be interesting in following up on or would there be any other steps or paths for this therapy that you think would be interesting?

Yes, I think it would be. Actually we found a bunch of antibodies. One group of antibodies that we found have killing capacity by themselves so when they bind to leukemic cells they actually kill leukemic cells without the help of other cells, without the help of complement. They are really killer antibodies by themselves. So those antibodies are very interesting. Also to further study the exact mechanism that they use because of course we could then, if we understand the mechanism, exploit that mechanism perhaps to kill AML cells. But also you could imagine that you use these antibodies as a therapy alone or perhaps in combination with existing therapies like standard chemotherapy for AML. Other antibodies that we’ve found are also interesting because that antibody is really binding to every leukemic cell that we could get our hands on and it’s really specific for AML so that would be really a candidate as a naked antibody like we use rituximab in combination with chemotherapy. We are testing that now in a mouse model but also that would be a really interesting candidate to further explore as an antibody-drug conjugate or for CAR T-cell development.

It sounds like it would complement checkpoint therapy very well as well.

Yes, definitely.

That answers all the questions I have prepared, is there anything else you would like to add?

I think it’s exciting and what is interesting, as I said at the beginning, what is interesting about this is that we as researchers did not decide what the target should be. We really exploited what is happening in nature and took that and learned from that and that really learned us a lot. Through doing that new targets were exposed and that is really what is exciting about this research.