CELLTHERAPY falling short of its potential?

Despite major investment in the field, few cell therapies have gained regulatory approval with limited commercial success.The success of therapeutic products is defined by three factors: safety, efficacy and scalability.Achieving these for cell therapy presents new challenges; overcoming transplant rejection (and GvHD in the case of immune cells), producing and culturing functional cells and developing an off-the-shelf therapy with a scalable manufacturing process.Gene editing technologies (CRISPR,TALENs and ZFNs) are paving the way towards allogeneic safety with numerous developments towards ‘universal donor cells’. However, such progress would be almost idle without the possibility to produce and culture mature (functional) cells at scale.A bioinformatics approach to systematically control the transcriptomic network with transcription factors and/or small molecules to culture or convert any cell type opens up the opportunity to develop any autologous, allogeneic cell therapies and a new class of therapies: in vivo reprogramming.


lassical pharmacology is broken. Despite having yielded some successful therapies, both clinically and commercially, designing

drugs and biologics based on target identification and hit/lead development is failing to systematically produce drugs. It is estimated we understand the mechanism of just 30% of small molecule drugs due to their lack in specificity and, most important- ly, our lack in understanding of systems biology. Cells, on the other hand, have been engineered by millions of years of evolution to respond to specific needs while in specific conditions. It is this potential that cell therapies are trying to harness. However, the development of clinically and commercially- successful cell therapies presents new challenges, namely bypassing the immune systemandmanufac- turability. Fortunately, owing to its potential, the field is seeing an enormous amount of investment and commitment to the development of technolo- gies such as gene editing and cellular engineering to

Drug DiscoveryWorld Summer 2019

surpass these hurdles. It is only when both of these hurdles have been surpassed that cell therapies will satisfy the levels of efficacy, safety and scalability required to realise its potential. Throughout this piece we will explore these challenges and the tech- nologies that are addressing them through a first principles approach. In the same way that beta-pancreatic cells pro-

duce insulin to regulate blood glucose levels, each cell in the body has evolved for one (or often sev- eral) specific purposes. This functionality can be harnessed in two different ways. Firstly, the cells can be used to target disease of a foreign nature in a more targeted and efficient way. This principle of ‘ex vivo acquired immunity’ is the one exploited by CAR-T therapy, whereby native T-cells are extract- ed and modified to recognise cancers. When re- injected the cells can, as a result of their modifica- tion, recognise the cancer and destroy it using their normal cellular functions. Secondly, cells can be


By Pierre-Louis Joffrin

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