The immuno side of melanoma

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Published: 16 Jul 2012
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Dr Antoni Ribas – UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA

Dr Antoni Ribas talks to ecancer at EACR 22 in Barcelona about advancements in immunotherapy in melanoma patients.


Recently two unconventional methods of therapy, dabrafenib and belimumab, have shown positive results in patients where they previously have not. 


Dr Ribas focuses on understanding the immunotherapy side of melanoma and the different approaches to use the immune system in fighting cancer.


The next step for immunotherapy is seen in recent studies of PD1 antibodies, which release natural brakes in the immune system that stop forced activation. The cancer cells in turn exploits these brakes making the therapy counter productive.


Also discussed is ipilimumab and its efficacy compared to other drugs that battle BRAF.

22nd European Association for Cancer Research, Barcelona, 8th July 2012


The immuno side of melanoma


Dr Antoni Ribas – UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA


Tell us about your speech on immunotherapy in melanoma?


It’s been a great time to work in melanoma, both on two sides, on the targeted therapy and immunotherapy, two modes of therapy that are non-conventional up until recently that are based on bringing science to patients and those two forms of therapy, both immunotherapy with a CTLA4 blocking antibody, ipilimumab, and targeted therapy with a BRAF inhibitor, regorafenib, are both showing improvement in the survival of patients for the first time in this disease. So I focussed on understanding the immunotherapy side of melanoma and what are the different approaches to turn on the immune system to fight the cancer.


How does ipilimumab compare with other BRAF drugs?


It’s the opposite kind of patient benefit; with the immune-stimulatory antibodies like ipilimumab there are very few patients who respond but those tend to be durable responses. I’m following a patient from the phase I trial of ipilimumab, which is going on for eleven years, and she had metastatic melanoma so that’s the kind of thing that we’re interested in where if the immune system works the right way it not only attacks the cancer but then it remembers and it gives these very durable responses as opposed to targeted therapies of blocking one oncogene and we have a high frequency of responses that tend to not be durable. The next step in immunotherapy for melanoma has been the recent publication of data with PD1 antibodies. PD1 antibodies like CTLA4-blocking antibodies are releasing a brake that the immune system has. For many years we’ve tried to turn on the immune system to fight cancer, well we’ve found that the immune system doesn’t like that, it has a whole bunch of brakes to turn itself off so we don’t have autoimmune diseases and the cancer takes advantage of that. One of these brakes is CTLA4 and that’s what ipilimumab targets; another break is PD1 which is a break that’s in the effector phase of immune response when lymphocytes that are being activated to fight the cancer reach the cancer and the cancer hides itself by expressing a ligand for PD1. It’s taking advantage of what evolution has developed for us to not have too much inflammation, for limiting inflammation. So we use antibodies that take away the receptor PD1 or the ligand PDL1, then we’re getting higher response rates than we had with any other immunotherapy before where responses are now around 30% of cases as opposed to 10% or less with ipilimumab and non-immune activators. Then the side effects are lower because it’s more targeted to the T cells that are fighting the cancer.


Can this approach be applied to tumours other than melanoma?


The even more impressive thing than this is that when used in patients with metastatic lung cancer, 20% of patients had responses. If I have to think of the history of oncology, if I had to think of just one case of an immune response to one cancer, I would have trouble doing that. Here we have reproducibly a group of patients with metastatic lung cancers that by taking away PD1 we start getting T cell infiltrates and responses.


What is the future for immunotherapy in cancer?


We’re making a lot of progress on understanding the fine details of how to modulate an immune response. So now we can start combining things, we can combine immune activators with antibodies that take away the brakes, like CTLA4 or PD1. We can also combine immunotherapies with targeted therapies, going back to what we were saying before, where we have with targeted therapies high response rates that don’t tend to be durable, if we want an immune approach can we make those high response rates maintain and then be durable? That’s something that the science is leading us to because, for example, for BRAF inhibitors we know that not only they don’t cripple an immune response to cancer but they may even make it better so it’s the next generation of combinations.