Cell Therapy, CAR-T Cancer cells
Cell Therapy - Falling short of its potential?

Cell Therapy - Falling short of its potential?

By Pierre-Louis Joffrin

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.

Classical 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 importantly, 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 commerciallysuccessful cell therapies presents new challenges, namely bypassing the immune system and manufacturability. Fortunately, owing to its potential, the field is seeing an enormous amount of investment and commitment to the development of technologies such as gene editing and cellular engineering to 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 technologies that are addressing them through a first principles approach.

In the same way that beta-pancreatic cells produce insulin to regulate blood glucose levels, each cell in the body has evolved for one (or often several) 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 extracted and modified to recognise cancers. When reinjected the cells can, as a result of their modification, recognise the cancer and destroy it using their normal cellular functions. Secondly, cells can be used to replace missing or malfunctioning cells. This is the principle of regenerative medicine. Because of the enormous potential of cells in both of these spheres, the field has seen upwards of $7 billion of investment in 2018 between the US and EU alone....

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