AACR 2015

New immunotherapy yields long-lasting responses in some patients with advanced melanoma

Dr Mark Middleton - University of Oxford, Oxford, UK

It is an immunotherapy but what makes it different from all the other immunotherapies is that it’s a highly engineered T-cell receptor that recognises small fragments of proteins presented by the body’s own immune system on the cell surface rather than with all the checkpoint inhibitors recognising a big full protein on the cell surface. It’s the first of many trials because the peptide that we’ve targeted is one that is found exclusively in melanoma, pretty much exclusively, it can also be seen in some tissues in the eye and ear and is also expressed in some brain tumours. So we went into melanoma because it’s a disease that traditionally has had some responses to immunotherapy and because we had a really good target to aim at.

What we did first of all, when we reported this here last year, was to slowly increase the dose of the IMCgp100 to find out what the maximum tolerated dose would be. We had some concerns at the start of the trial that we could trigger quite a significant immune response, a cytokine storm, and that could be very harmful to patients. So we had to take it very slowly, very cautiously, and it took us a couple of years to do that. Then this year we’ve come back to report the results at the maximum tolerated dose in this cohort of nearly twenty patients.

Can you explain to me what the two ends of the IMCgp100 do? One is described as a targeting end and another as an effector. Does that mean it’s like the guided missile with a bomb being delivered?

It is, it’s a little bit like that. So the targeting end is the guidance system, the effector end is the payload although in this case, because we’re using the immune system, we’re using the body’s own cells to deliver the payload. So the targeting end is very, very heavily engineered and binds very, very tightly to gp100 when presented on the cell surface so that it sticks there for hours on end. Then the effector end binds to passing immune T-cells, locks them to the tumour cell and that creates what we call an immune synapse and leads to the T-cells killing the cancer cells.

We saw relatively little activity, as we expected, very early on in the trial because the dose was low but as soon as we started to get up to doses that we could detect in the bloodstream we started to see tumour shrink, and that was very exciting. We’ve now, in the current cohort, have seen four patients whose tumours have shrunk, in two cases for nearly two years that benefit has been maintained and is ongoing. Also in two other cases we saw tumour shrink in patients with uveal or ocular melanoma which is extremely unusual because that has been a type of melanoma that has not really responded to some of the other developments in the field like checkpoint inhibitors.

What about toxicity with this new agent?

Clearly if you give enough of it it’s quite toxic; around the time of the first dose it causes quite an impressive skin rash. It can cause swelling as well in the fingers, of the hands, around the eyes and so forth, and some people’s blood pressure does drop a bit. We’ve got smarter at managing that as we go along so that now we’re pretty confident that we can get everybody through the first dose at 50μg without too much difficulty, although we do ask them to stay in overnight so that we can monitor them. Then what we find is that the side effects ameliorate very dramatically with subsequent doses so that we can give them as an outpatient.

Now, this is early days for your immunological guided missile approach but how is it comparing with, say, the checkpoint inhibitors which, of course, have done great things with melanoma very recently?

Sure. So our preliminary results show a response rate of somewhere around the 25-30% mark but obviously that’s on a very small number of patients. What’s very exciting, as well as the clinical activity, is the information that we’ve got about the biology behind it so that when we go and look at the tumour biopsies they show that the IMCgp100 is pulling T-cells into the centre of the tumour, is generating an adaptive immune response. What that holds out the promise for is successful combination with some of the other drugs you’ve mentioned so that together they can work even better.