Cassian Yee, Fred Hutchinson Research Centre
Chris - Recently researchers at the Fred Hutchinson Research Centre in Seattle have been using this approach to Ďcureí Ė Iím using this word very carefully. They have successfully managed to cure a patient who had malignant melanoma. Cassian Yee is the researcher whoís been leading this work. He joins us now, hello Cassian.
Cassian - Hello, how do you do?
Chris - Very well, thank you. How does this technique to persuade the immune system to attack the tumour really work?
Cassian - We use a process known as adoptive immunotherapy. That involves collecting white blood cells. The cells that you mention can fight infection but can also fight tumour and taken from these white blood cells, a population of cells known as T cells which specifically recognise the patientís tumour cells. In the lab we can isolate those rare T cells that can recognise and kill the melanoma cells. Melanoma cells express a target antigen. If we can expand enough of these T cells, we actually clone them as single cells, and introduce them back in the patient itís hoped that they can travel to the melanoma site and recognise and eradicate the tumour cells.
Chris - Why donít the T cells, if the patientís already got them to start with and youíre just increasing the numbers, why donít they go in there and wipe out the tumour for the patient without any help from you?
Cassian - Yeah, so thatís a very good question. For a long time people felt like perhaps these cells do exist in the body. It turns out that using specialised techniques to detect these cells they are present but in very low numbers. I think you mentioned earlier in the programme that the body sometimes suppresses the immune response against normal cells. Part of this suppressant mechanism may prevent these T cells from recognising tumours as well. Using The process of adoptive therapy weíre able to isolate these cells outside the lab and expand them without the constraints that might be present in the body that limit their expansion against the tumour cells. On top of that the tumour cells themselves have evasive mechanisms. They find ways to prevent the immune system from revving up and recognising them by releasing suppressive factors or by co-opting immune suppressor cells to prevent the immune system from recognising and expanding them. I think by removing them from that environment and putting them back in, in expanded numbers, we might be able to override some of these immune escape mechanisms.
Chris - One of the interesting things about treating cancers is that when you start to treat them, because cancers are already genetically deranged, in other words their DNA is all over the place, this means that cancers are not all the same and therefore some cells will be killed by certain therapies. Others will disguise themselves, look a bit different and they escape therapy because they evolve ways of being unresponsive to the drugs and so on. Why doesnít that happen here? Why donít you end up with a clone of cancer cells that arenít recognised by these immune T cells youíre putting back in and therefore they escape and put the cancer back?
Cassian - Thatís a very good question and thatís one of the major obstacles for immune therapy or any type of specific therapy. In this case we did originally do the study with one type of T cell Ė the CD8 T cells and found that had in some of our patients where the tumour cell was able to evade detection by suppressing expression of the antigen that was recognised by the T cell. In this case we used a different type of T cell Ė CD4. This T cell not only may kill the tumour cells directly by recognising this antigen but it may also recruit other immune cells that can kill in a non-specific fashion. One thing with the CD4 T cell which weíve expanded in the lab and given back to the patient goes to the tumour site. The CD4 T cell may release other chemokines or cytokines that bring to the tumour site other immune effector cells which may kill the tumour non-specifically regardless of whether they express the antigen levels targeted in the first place or not. By bringing to bear other immune effector cells we may be able to eradicate tumour cells whether they express the antigen or not. One thing we did find in the paper in some of our patients is that when this happened the tumour cell breaks down and because the CD4 T cell is present and causes inflammatory response other antigens are brought to light and the bodyís own immune response takes over and starts to direct its own T cells that we didnít grow in the lab but were already there to expand and grow and kill other targets on the tumour cell.
Chris - Whatís the risk, having said what you said, that you might end up with inappropriate attack? In other words if you look at certain diseases like thyroid disease or rheumatoid arthritis and certain types of diabetes thatís where the immune system is inappropriately attacking healthy tissue. If youíre priming the immune system like that and getting this spill-over to other bits of the immune system whatís the danger Ė or is there a danger that you might get an auto-immune disease and instead of just attacking tumours these cells then start attacking something else you donít want them to hit?
Cassian - Thatís a very good question. In part that might be limited by the local effect with the initial homing or trafficking of the T cells that we gave to the patients end up expanding. Thatís a local inflammatory process where weíve targeted the tumour specifically and it may set off an inflammatory environment that causes an immune reaction to occur. Thatís not to say that some of these cells canít travel to other sites and cause some auto-immunity. In fact we have seen some auto-immunity in patients where some of the target antigens on the cells are also expressed on normal cells. In the case of melanoma some of these targets are pigmented proteins so whatever is responsible for the colouration on your skin. When we start killing the tumour cells some of the T cells may also end up killing normal pigmented skin cells and we see a whitening, a lightening colour on normal skin. That type of autoimmunity is not too toxic. Itís still relatively safe in terms of patient discomfort. When we see this we also recognise that if patients have a high likelihood of responding as well to the immunotherapy. Whatís happening in the normal cells is also happening to the tumours. There is some auto-immunity but we think a lot of it is concentrated where the initial inflammatory reaction occurs.
Chris - Finally Cassian, youíve done this with malignant melanoma. Thatís an important problem because the numbers have gone up in this country at least 100% in the last ten years. Every Western country has seen lots of malignant melanoma but weíre also seeing lots of other cancers, particularly things like lung cancer. Will the same approach that youíve taken also apply to other types of tumours?
Cassian - Yes. Weíve taken melanomas as sort of a model tumour because a lot of the target antigens are known for it. We know that there are T cells are generated that will recognise those target antigens. It turns out there are also antigens that are shared with lung cancer, breast cancer and prostate cancer however a lot of those studies are in very early stages while people work out what the differences are in the conditions and what the timing of immune-therapy is for treating other types of cancer.