Therapeutics


bring immune effectors and tumour targets in close proximity also show promise, but each individual’s tumour requires costly screening to identify a tumour-specific antigen. This model is also depen- dent on the recruitment of a functional, non-senes- cent immune cell, although this may be overcome by co-administration of other therapeutics, such as ipilimumab or nivolumab, or immuno-stimulatory treatments targeting co-stimulatory molecules, such as OX40. What is most exciting is that personalised approaches are being adopted in cancer treatment. With the discovery of better biomarkers, lower-cost personalised treatments are more likely.


JS: Personalised medicine in the light of IO is mostly defined by designing the drug (cells, compound or vaccine) specifically targeted against the individual tumour. As IO is based on the idea that the body fights its own cancer, personalised medicine is a fun- damental part of this treatment strategy. This requires that the individual cancer is profoundly characterised to identify its unique weaknesses and druggable targets. This elaborate approach implies the possibility of a growing knowledge about tumour biology which might help us to identify pos- sible treatment strategies tackling common charac- teristics of specific tumour subtypes in the next five to 10 years. In parallel, the development of urgent- ly-needed predictive biomarkers will be facilitated.


What are the biggest opportunities for IO to improve patient outcomes? LB: Tumors have been classified as being immuno- logically ‘hot’ (eg melanoma) or ‘cold’ (eg prostate cancer), based on the degree and type of immune infiltrate. ‘Hot’ tumours are therefore relatively highly immunogenic, but to counteract this the tumour has developed a range of mechanisms to subvert this response. Checkpoint inhibitors work relatively well in the context of a ‘hot’ tumor as they can reverse at least some of the immunosup- pressive mechanisms to unleash the existing T-cell response, but they can be less effective in combat- ing immunologically ‘cold’ tumors, to which a T- cell response may never have developed. Immunogenic cell death (ICD) is a form of apopto- sis caused by chemotherapy agents such as oxali- platin or radiotherapy9. It is characterised by the detection of danger-associated molecular patterns (DAMPs) including extracellular ATP and surface- exposed calreticulin by tumour cells after induc- tion of endoplasmic reticulum stress. Such DAMPs drive dendritic cell activation and promote the development of an anti-tumour CTL response. The careful timing and use of combinations of


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chemoradiotherapy or oncolytic viruses in combi- nation with checkpoint inhibitors may render ‘cold’ tumours more immunogenic, and there is a great opportunity for IO to improve patient out- comes in both ‘hot’ and ‘cold’ settings.


JS: The deeper understanding of how fully- approved therapies influence the patient’s immune system opens the possibility for an endless number of combination approaches. Well-known treat- ments can be repurposed in combination, leading to increased patient benefits in a timely and safe manner. The possibility of targeting immune cells or other parts of the TME can prevent the develop- ment of acquired resistance against targeted thera- pies. Beyond that, it becomes possible to treat a tumour already heavily pretreated as the mode of action of a checkpoint inhibitor is largely indepen- dent of the altered signalling pathways within the tumour cell. The possibility of influencing tumour growth via


the microbiome is another opportunity to improve a patient’s outcome. Preclinical data is promising, but clearly indicate that like other strategies in IO, the mechanism of action is not fully understood. Finally, the knowledge around the importance of the tumour-stroma crosstalk for drug sensitivity as well as resistance is becoming more and more obvi- ous. Drugs targeting stromal cells and other com- partments of the TME beyond TILs are currently under investigation.


What are the biggest challenges faced by the field of IO right now? LB: In many ways, I think one of the biggest chal- lenges to those in the IO field is to determine which combinations of checkpoint inhibitors are best for each cancer indication, and for the individual. The success of ipilimumab, pembrolizumab, nivolumab and avelumab has meant that an unprecedented amount of money has been put into identifying novel checkpoint pathways and immune stimulato- ry modulators. There are currently 636 registered clinical trials involving nivolumab alone. Looking forward, therapies targeting a range of


other molecules such as TIM3, LAG3, IDO, CD39, CD73 or arginase will come online. As these new therapies reach the market, the potential combina- tions will increase exponentially, along with the costs, which will eventually be passed on to the patient. We are likely to see increases in the response rates of patients in combination trials, but the key challenge will be in identifying biomarkers that can enable the right combinations to be cho- sen for each patient’s tumour. When you factor in


Drug Discovery World Spring 2018


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