Dr Nicolay on Biomarkers and Mechanisms to Support Mogamulizumab

It looks as if anti-apoptotic proteins are upregulated upon mogamulizumab resistance, and therefore the hottest topic will be to overcome this new apoptosis resistance.

If a tumor can shed mogamulizumab’s target and keep growing, the next question is what to hit instead — and whether the answer is written in the cell before treatment starts or only emerges during it.

Jan P. Nicolay, MD, PhD, a cutaneous lymphoma physician-scientist at University Medical Center Mannheim and the German Cancer Research Center (DKFZ), is using single-cell sequencing to find the mechanisms that turn a responder into a non-responder — and thus, the next set of targets.

In a second part of his discussion at the 6th World Congress of Cutaneous Lymphoma (WCCL), Nicolay turned from how resistance arises to what biological readout could actually guide mogamulizumab use.

Nicolay’s group is just finishing its single-cell sequencing studies. The early signal, however, points in a specific direction: anti-apoptotic proteins appear to be upregulated as resistance to mogamulizumab develops. If that holds, the priority becomes overcoming this acquired resistance to cell death, since a tumor cell better able to evade apoptosis is also less sensitive to the antibody-dependent cellular cytotoxicity through which mogamulizumab kills.

He drew a deliberate distinction about what kind of marker he is chasing. Rather than searching for cell-intrinsic, pre-existing biomarkers present before therapy, his group is focused on the dynamic changes that unfold during treatment — developments caused by, or at least related to, mogamulizumab itself. It is a shift in emphasis from the static, preformed cell to the moving process of resistance.

Nicolay acknowledged limitation of current data. Many factors influence a cell’s death behavior and its sensitivity to antibody-dependent killing, and he is convinced they all contribute. Which one is the causal driver remains unresolved. That distinction, between the process that drives resistance and the noise that accompanies it, is the question his sequencing work is built to answer.