AACR 2016

Mechanisms of immune escape in non-Hodgkin lymphoma

Dr Riccardo Dalla-Favera - Columbia University Medical Center, New York, USA

I chaired the session that was titled Immunoescape and Immunotherapy for Lymphoid Malignancies. Now, lymphoid malignancies are a very heterogeneous group of cancers, over forty cancer types, and the goal of the session, essentially, was to address the issue. For the most common type of lymphoid malignancies, called diffuse large B-cell lymphoma, I presented evidence that tumours have adopted genetic changes to escape surveillance by the immune system. They delete or inactivate genes that produce molecules that are seen by T lymphocytes in order to kill tumour cells. These are irreversible changes because they are genetic and so over 50% of these tumours are invisible to the immune system. This is a simple direct way for tumours to evade surveillance.

In the second session Dr Shipp from Dana Faber showed for another type of lymphoid malignancy called Hodgkin lymphoma a different mechanism. Tumour cells put on their surface molecules called checkpoints that tell the T-cells, the immune system, not to attack them. So although the tumours are seen by the immune system they tell the immune system not to be attacked. The difference between the first scenario and the second scenario is that the first is irreversible, the tumour cell will be permanently invisible. In the second scenario you can intervene therapeutically and, in fact, antibodies deactivating these so-called ‘Don’t eat me’ signals by tumour cells have a dramatic effect in changing the clinical course of Hodgkin lymphoma. So that’s a major advance. This type of intervention is now used for other tumours, melanoma, lung cancer, but I would say Hodgkin cancer is the most dramatic success for the time being for this intervention. It’s not clear how long-term this will end up being but certainly there has been a change in the clinical course.

In the third presentation Dr Ron Levy from Stanford reviewed in an educational spirit for the audience all the different approaches that are currently being developed, again to either make the tumour more visible to the immune system or to tell the immune system to see the tumour better. He presented evidence of arming T lymphocytes genetically to recognise specific antigens on the tumour or bispecific antibodies that bring on one end the T-cell close to the tumour and with the other domain they kill the tumour cells. And he presented initial evidence on a multitude of clinical trials around the world that are developing these strategies, some with initial very good successes in B-cell malignancies.

Could you summarise your talk on attracting T-cell response?

The tumour cells are making themselves invisible by putting up molecules that tell the T-cell ‘Don’t attack me’ whereas in the first, in diffuse large cell lymphoma, they make themselves invisible by inactivating the molecules that usually are seen by T-cells. So there are a variety of mechanisms.

Could you tell us about the “inactivating checkpoint” approach?

Inactivating the so-called checkpoints is becoming a widespread approach in many types of cancer with, as I mentioned, initial success in melanoma and lung cancer. But certainly it is an approach with broad utilisation. The first one, the simplest one, genetic inactivation of molecules, is difficult. It’s irreversible and probably this poses serious challenges to make the immune system more active because the tumour cells are seen as self.

Are there risks in treatments that stimulate auto-immune response?

Yes, if you wish, if you re-arm the immune system towards the tumours you would mimic an autoimmune response but for a good end in this case.

What do you think the headline will be at AACR 2017?

There is an enormous attention to immunotherapy of cancer after decades of slow progress. I think there are three areas of major development, the first, as I said, bispecific antibodies that connect T lymphocytes, the weapons, to the targets, the tumour cells. The so-called CAR T technology that also modifies T cells, the weapons, to attack better. The third, which is the one that is attracting a lot of attention, is based on the fact that the genetic mutations that make the normal cells become a tumour generate a number of so-called new antigens, neoantigens, that are recognised as new by the immune system. So you can use these neoantigens as vaccines for arming the immune system. This is more complex and long-term, most cases will be different, one from the other, but rationally it makes a lot of sense.

What is your take-home message?

As a conclusion I would say we are entering a very exciting area of immunotherapy of tumours, as I said, after decades in which this field was dormant. A lot has to do with major development in technologies that allow to modify effector cells, immune cells, and to identify new molecules that are non-self in the tumours. The technology is exploding and following that there are new approaches every day. I think the next few years will see a lot of progress, this is just the infancy of this emerging field.