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Therapeutics


therapies in which cells are extracted from one patient, grown and implanted back into the same patient. This suited Holoclar and ChondroCelect as the treatment aimed to regenerate a small and dam- aged proportion of tissue using cells fromthe healthy portions. The recently-approved CAR-T therapies KYMRIAH and YESCARTA still use this principle to attack cancers,with the patient’s own T-cells being modified ex vivo and reinjected. Bypassing the immune systemwith these therapies, however, comes at the price of one of the key performance indicators: scalability. While the therapies are mostly safe, hav- ing to extract and grow cells for individual patients under GMP conditions is extremely expensive, logis- tically complex and,most importantly, does not scale in the same way as having an off-the-shelf product. As a result, therapies such as KYMRIAH cost $475,000, while therapies that cannot justify such a high price tag to support a GMP facility (eg ChondroCelect) are withdrawn because of a lack of commercial interest. Owing to these factors, the field of cell therapy


has, in the past decade, shown a clear trend towards the development of allogeneic therapies, in which cells are extracted from one patient and implanted in another as an off-the-shelf product. For cells to be implanted allogeneically, they need to be modified to remove the HLA complexes on their surface, making them ‘invisible’ to the immune system, and therefore tolerated by the host. This requires an acute knowledge of the immune system and highly specific gene editing technology. Fortunately, leaps and bounds have been made in both of those fields, with many companies now leveraging different technologies in an attempt to


create ‘universal donor’ cells, akin to the O-nega- tive blood type which can be perfused into any patient in case of blood loss (a much-forgotten example of cell therapy). Notable examples include Celixirwith its immunomodulatory progenitor cells (iMPs), recently-acquired Juno Therapeutics using its clustered regularly interspaced short palin- dromic repeats (CRISPR) technology, Cellectis with its transcription activator-like effector nuclease (TALEN) technology, and Sangamo therapeutics using its zinc finger nuclease technology in collabo- ration with Gilead (Kite Pharma). However, in the case of Sangamo, Cellectis and


Juno, avoiding transplant rejection is not the only hurdle when developing CAR-T therapies. As immune cells, the T-cells injected also have the innate ability to recognise foreign cells (such of those of the host in the case of an allogeneic thera- py) and destroy them. This is known as grafts-ver- sus-host disease (GvHD), which can cause major adverse effects and, in many cases, death. To avoid this, these innovators also have tomodify the T-cell receptors (TCR) or CAR-receptors used to avoid recognition of any healthy human cells while still recognising the cancer. Cancers having initially evolved from the body, this finely tuned level of specificity is very hard to achieve. It is worth noting that there are some cases in


which little-to-no genetic modification is required to create an allogeneic therapy. Organogenesis’s GINTUIT is an FDA-approved cell therapy prod- uct, developed for surgically-created vascular wound beds in the mouth using allogeneic human cells (keratinocytes) and bovine collagen. This product has shown satisfactory efficacy in 50%of


CAR-T cell (red) killing cancer cells


Drug DiscoveryWorld Summer 2019


47


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