EMCC 2011

Effects of radiotherapy on the immune system

Dr Silvie Formantini – NYU Langone Medical Center, New York City, US

Silvie Formantini from NYU, thank you very, very much for coming in; it’s been a long haul, I hope you’re not too jet-lagged.

Not bad.

Tell us about what you’re doing here?

I’m speaking, actually, I just spoke at a very interesting session that was talking about the effect of radiotherapy on the immune system. This is a completely new merger of immune therapy and standard treatments, chemotherapy and radiotherapy. This meeting is covering it quite extensively, so it’s really interesting.

It’s completely new isn’t it?

Completely new.

We know that radiation kills off immunity, or so they say.

That’s right.

But you’re reviving it?

We’re reviving it. So we’re looking at it from a different point of view. Radiation is a very powerful way to destroy the immune system when it’s given to the entire body but what is known less is what is going on when you irradiate one tumour and how is the immune system sensing that effect, the damaging effect, on the tumour you are irradiating? So the question is, and with chemotherapy it is a little bit different because it’s a systemic effect, radiation is just a very local effect. So can the tumour now become an interesting immunogenic hub, so a site where you can somehow recover the blindness of the immune system? Of course there wouldn’t be a tumour if the immune system were capable, was working well, it was capable to reject the tumour. So by the time the tumours are established, they have escaped the immune system. So we are trying to see whether we can use radiation to help the immune system and maybe with some immune therapy recover the recognition of rejected tumour.

What sort of immunotherapy have you in mind?

We have been working pre-clinically with a very now famous drug, an interesting drug, which is ipilimumab which is an anti-CTLA4 antibody. We’ve done it in the mouse model and then we tried different brakes in the immune system, so we tried to inhibit TGFß, we did it with fresolimumab, which is another antibody, again in a mouse model. We used a model, of course you want to work on preclinical models where the animal is immune competent because you want to really try to mimic what’s going on in reality and patients, as you know, have a pretty good immune system except for their blindness against the tumour.

I was talking earlier to the melanoma boys about ipilimumab in combination with chemotherapy and they were saying that already in melanoma they have data that suggests that ipilimumab works best combined with immunogenic chemotherapy. So that’s actually what you’re doing.

Right. So there is work done by others, actually very interesting work done by the group of Widdicombe.

Yes, that’s the work.

And they were really able to, in a very elegant series of experiments, to show that some drugs but not all of them and definitely radiotherapy are capable to induce cell death, we knew before, but a type of immunogenic cell death, so a kind of cell death that is also sensed by the immune system. And there are other drugs instead that make this tolerogenic cell death, so they may work against the immune system recognising the tumour. So it’s really a new way to look at oncology.

It’s a completely new paradigm for me.

For everybody I think, definitely. Because the beauty of recruiting the immune system in the game is that once the immune system recognises a target, then it establishes a memory and a capacity to continue to come back and sustain the destruction of that target. If you are able to do that in cancer treatment it would be great, and now there are counterparts because cancer is also capable to escape the immune system, so can develop and get smarter than the immune system. But I think you could re-immunise the patients against those tumours.

Presumably you’re doing timing and scheduling experiments in the mice, any clues yet as to how to do this best?

Yes, when we worked with ipilimumab, we noticed that we wanted to first use the radiation to kill the tumour cells. The beauty about radiation is that radiation in the process of inducing cell death has shown to be capable to promote cross-priming so this part of this loop of creating an immune response requires different agents, different cells. So there are these patrolling dendritic cells in the tumour microenvironment and so you break down the tumour cells into little pieces, antigens, or the tumour cells can be picked up in an effective way by dendritic cells.

Which are quite radioresistant, as I recall my physiology.

Yes, they manage to be around and be available. So that first step, and in our group and other groups have also shown that radiation is capable to induce MHC class 1 in tumour cells so that’s also helping. So there are new roles of ionising radiation that really are promising for this group and, of course, you start with a cross presentation and then if you’re successful in inducing an immune response you have a population of T-cells that selectively would recognise a tumour and then the other advantage of radiation, and that’s what my talk was about, is that radiation facilitates the migration of these T-cells by inducing a specific, it’s called chemokines, or an attractant for these T-cells to go to the tumour site.

What sort of model did you use to show that?

The 41 is a syngeneic murine mammary mouse carcinoma that very much mimics the setting of… the clinic, of course, is an artificial model so for the time you inject the tumour peripherally, so it’s not a spontaneous tumour model but very fast, in a very expedite way, this primary tumour spreads to the lung and eventually killed the mouse. So the idea is that if you irradiate the primary tumour, irradiate the microscopic tumours in the lung and you’re going to follow the number of metastases in the lung and the survival of the mice. And we showed that if you just give radiation you are not going to change the course of the life of these mice but if you give radiation and block the CTLA4 receptor, which we have a murine version of ipilimumab and it was a gift of Dr James Allison that allowed us to do these experiments. Most of these experiments were done in collaboration with scientists at NYU, I’m a clinician, as you know, so Sandra Demaria that I think you met when you came and visited and Mike Dustin and then we’re very fortunate with outstanding immunologists that helped us in this process.

So Silvie, you’re going into the clinic in breast?

Yes, we’re going into the clinic in breast and we chose to use fresolimumab which is an anti-TGFß, and again we’re very lucky, we got big support from the Department of Defence. You know the Department of Defence in the United States allocates some money for breast cancer research so, in collaboration with UCLA, we’re going to do clinical trials in metastatic breast cancer where we irradiate one lesion and then give fresolimumab, an anti-TGFß antibody, because TGFß is shown not only to interfere with radiosensitivity of cancer in general but also is another brake in the immune system. So we’re trying to remove that brake and we have preclinical data showing again that we can inhibit metastasis and prolong the life of mice. We’ll see whether we can do it in human beings.

I think it’s terrific, I think it’s better than a lot of the studies that are being done by the so-called medical oncology people here.

I don’t know if you can say that!