Immunotherapy in melanoma

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Published: 1 May 2014
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Dr Adil I. Daud - University of California San Francisco School of Medicine, San Francisco, USA

Dr Daud talks to ecancertv at the AACR conference about his work with immunotherapy in melanoma, specifically the PD-1 pathway and how, when disabled, cancer cells are prevented from penetrating further.

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AACR 2014

Immunotherapy in melanoma

Dr Adil I. Daud - University of California San Francisco School of Medicine, San Francisco, USA

Can you tell us a little about the work you’re doing with immunotherapy?

Sure, so one way of thinking about it is that our immune system is constantly surveying for the presence of cancer and cancer needs to find a way around the immune system if it is to grow. One of the ways it does that is by co-opting this pathway, the PD ligand PD1 pathway, which basically is used to turn off inflammation or turn off the immune system. So what can happen is that tumour cells or sometimes tumour stroma can start expressing PD ligand which kind of functions as a ‘don’t eat me’ signal so it tells your T lymphocytes not to attack or turns them off when they try to get rid of the cancer cell. So if you disable this pathway you’re basically taking out one method that cancer cells use to go around the immune system and it lets the immune system get at them. Then that’s what the PD1 antibody, which is what MK3475 is, accomplishes. So what we looked to do in this study is to see if PD ligand expression on tumour cells could be a predictor for response. What we found is that in concordance with previous studies it is a predictor of response, however it doesn’t have as much clinical utility just because even unselected patients, even patients in whom you don’t use this assay, have such a high level of response that once you do your PD ligand staining and even if you try hard to separate out the PD ligand positives and negatives as carefully as you can, you still end up with the situation where you go from 40% in unselected patients response rate to 47% in PD ligand positive patients. Then conversely, looking at the negative side, PD ligand negative tumours, you still have patients who respond even if you use 1% which basically means that even if one out of a hundred cells shows any sign of PD ligand staining that’s considered positive, even in the negative group you’re still preserving a fair amount of responders, 13%, which is actually one of the more active immunotherapy regimens out there.

Where do you  measure PD1?

PD ligand is measured on the tumour, usually on a metastatic tumour. In our study patients have to have biopsies of the metastatic tumour. It’s not totally clear today whether the primary tumour and metastatic tumour whether you would preserve that PD ligand status over time or whether it might change.

Do you look at PD-1 after treatment?

We looked at PD ligand in all kinds of situations but the data for which this study was based on looked at metastatic tumours only, PD ligand standing in metastatic tumours only. It’s not totally clear today whether primary tumours and metastatic tumours are comparable or whether PD ligand status changes over time or  treatments or whether chemo or ipilimumab or other treatments could even change that. So it’s not totally clear whether that’s a consistent thing.

Your work showed a good response rate but the survival rate was not quite so good?

What that data is showing is that even though there is a major difference between PD ligand positive and negative tumours in terms of their progression free survival, the overall survival was not different in the two groups. Part of that has to do with the fact that the anti-PD1 antibody works even in the PD ligand negative patients. So the difference between the two in terms of overall survival is just not a major difference. Part of it also is to do with the lack of maturity of this data. Basically those survival curves haven’t matured enough or patients haven’t been followed long enough for us to be able to tell whether there might or might not be a difference sometime in the future.

Could this be applicable to cancers other than melanoma?

Yes, and Dr Gandhi who just presented right after me was showing this very exciting data in lung cancer showing that lung cancer, which has previously not been thought of as an immunotherapy responsive tumour, actually has pretty dramatic responses also to PD1 antibody and there’s studies ongoing in other types of cancers including squamous cell cancers and other solid tumour malignancies like breast cancer. There are studies going on in haem-malignancies also. Probably this is a pathway that’s activated, that’s co-opted by a lot of different cancers, not just melanoma. Melanoma just happens to be the stalking horse or the tumour type in which a lot of immunotherapy is tested first but it’s like anti-angiogenics, like a lot of cancer therapy, once it works in one tumour type it’s often found that it’s more generalizable.

What will the next steps be?

Looking at more data and starting to build on this foundation of PD ligand status, looking to see what other factors contribute to response rate, I think that’s next for us.

Are there any other interesting immunotherapeutic agents being presented?

Yes, there are a lot of interesting data being presented on PD ligand 1 antibodies, on combinations. I personally am interested in interleukin-12 which I think has a lot of potential too. People are looking at checkpoint inhibitors or checkpoint blockade in combination with PD1 and it’s going to be exciting to watch this field over the next few years.