14th International Medical Education Workshop on Molecular Targeted Therapy of Cancer (MTTC)

Importance of the immune system in cancer

Prof Leif Håkansson - Linköping University Hospital, Sweden

We need to realise why the immune system doesn’t work in cancer. It’s quite clear from several results, to some extent our own and also by the group of … in France, that the immune system plays a major role in controlling cancer. Interestingly, looking into this kind of immune mechanism basically defined by … the immune score in a multi-variant analysis is found to be a lot more important than a classical TNM classification. So when it comes to prognostic testing of cancer we are in for a revolution. Immune reactivity against the cancer, immune status, has to be included in the prognostic information.

Is this something that happens regularly?

It’s developing now, it’s developing now, and that is one very important information that the immune system really is of key importance. The thing then is why doesn’t it work in cancer, in metastatic cancer? The main reason is that there are extraordinarily strong suppressor mechanisms acting, basically mechanisms which are there to protect us from our immunity. We start to understand them, obviously there are also mechanisms which are so far not identified and we are on our way to track them. So, for the future, being able to eradicate immunosuppression, I think that we can achieve a lot more in cancer treatment. Interestingly, this will not be true only for immunotherapy; it’s quite clear that the immune status is of paramount importance also for efficacy of other treatment modalities like cytotoxic treatment, molecular targeted therapy etc.

Are you specifically working on immunotherapy?

I’ve been working on immune therapy for a long period of time and you can look at this in different ways. Because there are so many mechanisms suppressing the immune system in cancer and the question is should we try to change every one? We know that if we correct CTLA4 inhibition or PD1, as you said, or PDL1 we achieve rather limited overall responses. Interestingly, these often translate into an amazingly good survival benefit but still it’s a minority of patients who respond. So the question is how is the immune system downregulated by the tumour? I think it’s quite possible applying the so-called immune editing model where we are talking about the first phase, elimination of cancer, then we have an equilibrium phase, the balance being the presence of cancer and activity of the immune system, resulting in no tumour progression. And finally something happens and we have escape and progressive tumour. By applying this system there are two transition points which are crucial. One is between the elimination phase and equilibrium phase, we can’t do very much about that because we can’t diagnose it, but we can do a lot about the second one between the equilibrium phase and escape phase. If we analyse the possible mechanism acting there we can reduce the mechanism considerably and set out for quite new therapeutic strategies.

Is there any evidence as to why most patients do not respond to immunotherapy?

Because most of the patients have advanced tumours, they have spread metastatic disease so they have what you could call a full-blown immunosuppression. There are so many mechanisms active and you had to correct so many of them to be successful. That means an extensive combination treatment to be successful unless we can start early on when there is a limited number of mechanisms which derange the immune system. So in my mind, in my view, it’s clearly an evolution of immune suppression in cancer and what we have when we start to treat is a very limited number of patients who have not yet developed the full-blown immunosuppression. Those can be… in those patients the immune system can be reactivated to control the cancer.

Will you be using it in combination with other treatments?

Hopefully it will be enough and that is based on our results. We can demonstrate the immune parameters; if they are fulfilled by the patient they do not die from the cancer, even if they have regional lymph node metastasis, similar to results from …, as I mentioned. So obviously under the right conditions with immune status you have a good cancer control. On the other hand, I think also that cancer is a very complex disease and it might very well be that combination treatment will be very efficient, in particular if we are going to treat rather large tumour burdens then there is quite an interest to reduce the tumour burden using surgery, radiotherapy and various kinds of cytotoxic and cytostatic drugs.