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Therapeutics


Every step of the cancer immunity cycle reveals distinct insights


although we were using the same in vitro assays we had developed to model autoimmune disease, there was now a drive to enhance, as opposed to suppress, inflammation with novel IO drugs. In optimising these assays, we often had to dial back the stimulus to open the therapeutic window. In turn this meant we had to completely invert the way we were think- ing; for instance, where we had been trying to expand regulatory T cells (Treg), we were now test- ing therapies aimed at inhibiting the same cell type.


JS: Coming from an oncology background, mainly developing targeted therapies, I had to get used to the idea that there were no available biomarkers at the time to aid in selecting the model with the high- est potential efficacy. Not only did the in vivo model have to be adapted to a new mode of action, it also changed the read-out; besides tumour cell killing, immune cell proliferation, dissemination and differentiation also had to be evaluated in the in vitro and in vivo models.


What have you learned from the other discipline (either immunology/ oncology) that you wish you knew earlier on? LB: It is fascinating and challenging to understand the breadth of mechanisms by which different tumours evade immune responses. For example, cancer cell immune-editing drives the generation of tumour vari- ants resistant to immune cell recognition. The major histocompatibility (MHC) class I pathway mutations can allow cancers to become defective in antigen pre-


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sentation to tumour-specific T-cells, and tumour cells can also induce tolerance, apoptosis or exhaustion in tumour-specific effector cells4-6. Secretion of immunosuppressive factors such as


prostaglandins, TGF and VEGF drive the genera- tion of ‘less effective’ immune cells, including myeloid-derived suppressor cells (MDSCs) and Tregs. While these effects are hurdles, they also represent opportunities for the identification of novel targets. To be involved in a field with such a wealth of novel targets is unprecedented and is driving the huge interest in reprogramming these cell types, or inhibiting their function, to generate robust anti-tumour immunity.


JS: It is exciting to learn more about the complex multi-dimensional interactions different immune cell types can perform. To generate a resourceful immune response while maintaining self-tolerance, the immune system is tightly regulated through a combination of stimulatory and inhibitory signals. How to influence this balance in an immuno-onco- logical context and to understand how many dif- ferent factors play a role in this complex biological system is an ongoing effort.


Did you have any misconceptions about the other discipline? What made your thought process change? LB: It took me a while to realise that the revolution in oncology had started and that there was a key role for conventional chemo or radiotherapeutics, not only in driving tumour cytotoxicity, but also in


Drug Discovery World Spring 2018


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