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Part III: Immunotherape of Melanoma and potential new targets besides PD-1

Round table discussion on immunotherapy of melanoma and potential new targets besides PD-1, between the editors of the Melanoma Resource Centre: Prof Reinhard Dummer (Professor of the University of Zurich and Vice-Chairman of the Department of Dermatology

Melanoma Topic 3 final

Prof Reinhard Dummer, chairing this session, introduces the topic of immunotherapy. Over the past decades, immunotherapy has evolved from a therapy that still remains to be proven effective, to a very promising new field. Dr James Larkin is asked how he has experienced these developments. He was delighted with the big progress since his start at his current position (in 2007/8), that was first marked by the results with KIT, B-raf, T-cell checkpoint. Previously, immunotherapy meant using cytokines that had a relatively small effect and were often quite toxic. Now with T-cell checkpoint inhibitors like anti-PD-1 and anti-PDL-1 drugs you have well tolerated drugs that can be delivered in the out-patient setting and have pretty strong signals of efficacy. Also, James is very pleased with the fact that these drugs also work for other tumors, besides melanoma and kidney cancer that always were considered as cases for which immunotherapy should be effective. Prof Dirk Schadendorf adds that in these other fields, besides e.g. melanomas, there has been skepticism for a long time, which has only recently been breached by clinical data showing efficacy beyond / on top of current treatment options, e.g. in patients pretreated with ipilimumab (anti-CTLA4), and prolong survival. The current enthusiasm for anti-PD-1 is fully based on the assumption that it is at least as good as ipilimumab. This is indeed what we see in clinical practice, but we do need to wait for the final results of these pivotal trials to be able to substantiate the enthusiasm. Reinhard expresses his amazement on the level of clinical effect one is able to get by targeting just a single checkpoint molecule (PD-1), especially when one realizes the number of molecules involved in these pathways. He stresses more research on understanding the T-cell – tumor interaction is likely to uncover more highly potent drug targets.

Reinhard asks James what other molecules can have a future for immunotherapy? Immunotherapy is hot now, with interest from scientists, clinicians and pharma companies alike. Most companies are now acquiring portfolios of T-cell checkpoint inhibitors. Most of such molecules are actually targetable. We do need to know more about the biology to understand the mechanisms. Especially for melanoma, as advanced melanoma are actually quite rare. Therefore, you will have to be smart about selecting the combinations to test, as the number of patients to test it on will be a limiting factor. James recons LAG-3 might be an example for the future, but there are others, all in clinical stages of development. In the last years, combining targeting drugs for kidney cancer has been a failure, leading to toxicities without increasing efficacy. James believes we will be able to do better in melanoma, but clinical efforts have to be based on rational science. This is the key to making further progress, which is still needed. Also, as every patient is different and may benefit from a different approach, we have to use what we can to provide every individual patient with the best possible outcome. For instance, we can now say to a patient “if you make it to three years on ipilimumab, there is a good chance we can get you to five years with anti-PD-1 after that”. That is a big change. Dirk concurs that it is a big change that we are now talking about long term survival with these patients. If we focus on the immuno-oncology field, Dirk thinks the most promising molecules are the antibodies targeting the immunological checkpoints. Several are in phase 2 or 3 clinical development for various cancer types. Of other immunological approaches that are being developed the most advanced is the CAR (chimeric antigen receptors) approach, but do we think we still need to deal with adoptive cell transfer or CAR approaches if we have all these different antibodies against checkpoints? James finds this a very good question, but does speculate that it is very likely that there will be patient populations that will benefit more from other approaches, as there is this diversity from patient-to-patient. So, despite certain approaches will be more complex, they may very well be valuable for certain patient populations. It does feel now that we have the tools at our disposal, and can begin to make progress – although a lot of work still needs to be done.

Reinhard concludes that the audience is now feeling the excitement, has understood there is a lot of progress, and there are many things to come. He is inviting all viewers to keep following the Advances in Melanoma Resource Centre, and thanks his colleagues for the discussion.

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