Using adoptive cell therapy to fight cancer

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Published: 11 Nov 2016
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Prof Malcolm Brenner - Baylor College of Medicine, Houston, USA

Prof Brenner talks to ecancertv at the EurocanPlatform Summer School on translational research about the uses of adoptive cell therapy.

In particular, he explains his work looking at the use of T cells to fight lymphoma.

 

I’ve been giving a talk about the uses of adoptive cell therapy, that’s taking cells from either the patient or a close relative of the patient and putting them back to treat cancers. The original sort of adoptive therapy was called bone marrow transplant or stem cell transplant. It’s now clear that one of the ways that that cures cancer is by a so-called graft versus malignancy effect so cells in the graft act against the cancer and eliminate it. There’s a whole variety of cells in the graft that can do that but the cell type that we have been focussed on has been T-lymphocytes.

Really for about the past twenty years we have been using these to attack malignancies in patients. I think probably it’s clear that one type of malignancy, in particular B-cell malignancy, is very amenable to cellular therapy and that’s true whether you use the conventional receptor on the T-cell, the so-called T-cell receptor TCR or put in an artificial receptor, the so-called chimeric antigen receptor. So a lot of attention recently to CD-19 targeted chimeric antigen receptors which are very effective at removing leukaemia and lymphoma. We have been using the native T-cell receptors to remove Epstein-Barr virus associated lymphomas and those form about 40% of all lymphomas. It works very well, broadly comparable.

Now the challenge is to move it outside B-cells and into other solid tumours because those are much more resistant to immune attack. What I have been talking about is the reasons why they are more resistant and the ways in which we can overcome it. The reasons they are more resistant are that they don’t have good antigens expressed; the antigens fluctuate all the time. The second is that they don’t give the right go signals to the T-cells, the so-called co-stimulation. The third thing is that they produce and have present a whole lot of cells and molecules that turn off the immune response. So our work has been focussed really on overcoming those three problems.

There seem to be some interesting things happening with stem cells…

Stem cells, cancer stem cells are different, obviously, to the mature cells in many tumours. They express different patterns of antigens and are sensitive to different drugs so if you can make them more amenable to being attacked then yes you could use the immune system. Certainly, one of the important things that you have to do is make sure that when you’re targeting a cancer with an immune attack that you also target the stem cell population. But to do that you first of all have to identify the stem cell population and see what its markers are.

Has the technology advanced much lately?

I think mostly what I was talking about was how we’re applying it now to solid tumours and how we’re using T-cells that are targeted to a lot of different antigens on the solid tumour at the same time. Then these generate a nice immune response which is an evolving immune response. Because there’s a lot of activity what happens is you start generating new specificities even above and beyond the ones that you put into the patient. So you get what’s called antigen spreading and are more likely to be able to cope with an evolving tumour. Then I talked about how we’re adding different co-stimulatory signals and blocking the inhibitory signals by genetically engineering with T-cells.

What makes this meeting different from others?

I think what I like about it is there’s two things: first of all it’s small-sized, so people can actually talk to each other. Secondly, the fact that it covers a broad range of topics, rather than focussing in great detail on one topic so you get a view of where the field as a whole is going. And third, of course, because the students are here and I think it’s always good to have challenging questions put to you by people who don’t accept all the dogma and who are really looking for new ideas and challenging the old ones. It gives you an opportunity to talk to people who are doing something slightly different to you but potentially overlapping and arrange new collaborations.  Also a chance to recruit good junior scientists.