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Christian Blank

Interview with Dr. Christian Blank, Staff Member of the Medical Oncology Department, Group Leader at the Division of Immunology at the Netherlands Cancer Institute (NKI/AvL) in The Netherlands, on melanoma immunotherapy approaches.

Dr. Christian Blank Interview

Interview with Dr. Christian Blank, Staff Member of the Medical Oncology Department, Group Leader at the Division of Immunology at the Netherlands Cancer Institute (NKI/AvL) in The Netherlands, on melanoma immunotherapy approaches.

Q: Is there still a role for interferon-alpha in melanoma therapy

The discussion on interferon-alpha in melanoma adjuvant therapy is going on for already a long time. In general we regularly see a minor effect of interferon-alpha for overall survival, but this is not above 5% when meta-analysis is done. This causes big differences in the use of the drug, e.g. in Germany it is widely used, but in the Netherlands it is not used at all as adjuvant therapy.

Dr. Blank however sees a future for interferon, which is based on the mechanisms interferon can induce. For one, it can upregulate the MHC molecules on melanoma cells and thus improve the presentation of tumor antigens. On the other hand, it upregulates PD-L1 expression, which is the flip side of the coin. It is the combination of interferon with antibodies that for instance target PD1 or PD-L1 that to Dr. Blank’s opinion have the future.

Q: Which are the most promising immunotherapy approaches?

Currently, the T-cell checkpoint blockade by anti-PD-1, -PD-L1 and -CTLA-4 mAb is the most promising. We already have ipilimumab (anti-CTLA-4 mAb) as a standard treatment for melanoma, and the data we have thus far seen for anti-PD-1 and anti-PD-L1 are even more promising. Therefore, Dr. Blank believes that the T-cell checkpoint blockade approaches have the best papers to become part of standard treatment in the near future.

Q: Is adoptive cell transfer with tumor infiltrating lymphocytes still useful?

Yes, although we still need to see what the real response percentages are. Many stage 1 trials have been seen, and patient selection is very important in relation to the response rates. NKI/AvL colleague Dr. John Haanen (Head of the Division of Medical Oncology) is setting up a multicenter randomized phase II trial, comparing a tumor infiltrating lymphocytes (TIL) trial with ipilimumab. TIL has a standing in the future, as gene-modified T-cells or in combination with T-cell checkpoint blockade, as with the latter alone we still see only 40-50% of responses.

Q: What will be the role of immunotherapy in the adjuvant setting of melanoma therapy in comparison to the palliative setting in advanced melanoma?

We are waiting for the ipilimumab adjuvant trial, to see how much benefit the patient has from this treatment. There are some adverse events, which are even more important in an adjuvant stetting than in a palliative setting. But, if we can, even in a small proportion of patients, prevent progression to stage IV disease (for which we have no treatment), in that light immunotherapy in the adjuvant setting will have an important role.

Q: Which patient will benefit from immunotherapy biomarkers?

Thus far we do not have the clear-cut biomarkers, as we do have for certain targeted therapies. For ipilimumab there is some retrospective data indicating that the outcome for patients able to complete the full 4 courses of treatment is better than for those only achieving 2 or 3 courses. Our group has identified LDH as a biomarker that is simple to measure. High levels of LDH were indicative of limited benefit from ipilimumab, while normal levels correlate with a greater benefit. Some other cellular markers exist, which possibly can be used in combination with LDH to stratify patients that will have the most benefit from ipilimumab. There are some data that show better response in patients with a PD-L1 expressing tumor. However, these data should be considered carefully, as PD-L1 is not a black-and-white marker, as it can be up- and down-regulated by the tumor. PD-L1 expression should be studies more carefully at the base line, to determine if and how this can be exploited as a marker for the future.

Q: What are, in your opinion, the perspectives?

Many interesting studies and combinations will be seen in the future. First we will combine immunotherapies. Already we see more depth in the response when combining anti-PD1 with anti-CTLA4 treatment, still we have to wait for the data to determine patient benefit. In light of the adverse events seen, it is expected to be possible to add other co-inhibitory molecules that are blocked, or stimulating other co-stimulatory molecules, to get triple or quadruple immunotherapies. But also e.g. cellular therapies can be combined with immunomodulating therapies, as well as targeted therapies with immunotherapy. In this light it is important to study cooperative activities, but also to study the sequential effects of different therapies.

Q: What are the general recommendations for treatment?

We currently have ipilimumab, with the characteristic that it can take some time until you get responses, but if you get responses you can have long-term benefit. Also we have the BR





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