Personalised medicine

An ongoing clinical trial of Holoclar, the first stem cell therapy approved by the European Medicines Agency (EMA), continues to demonstrate the effectiveness of transplants of cells cultured and expanded ex vivo for treating limbal stem cell deficiency (LSCD) due to chemical burns and other injuries, Graziella Pellegrini told the 37th Congress of the ESCRS in Paris, France. Prof Pellegrini presented the cases of two typical Holoclar patients from the current study, which involves 19 sites in eight European countries. One year after treatment, one adult and one child each recovered 9/10 best-corrected visual acuity and clear corneas from counting fingers and hand waving, respectively, due to complete coverage of the cornea by conjunctival tissue. These results are largely consistent with an earlier study showing stable, clear corneas for patients for as long as 10 years after treatment, with 76.6% achieving permanent corneal restoration (Rama P et al. N Engl J Med 2010; 363:147-155). PERSONALISATION AND PROCESS CONTROL The current open-label prospective trial, scheduled to conclude in late 2021, is required by the EMA to generate additional clinical data on Holoclar following its conditional approval in 2015. It is part of a broader data collection effort including sites across the continent and UK using the treatment commercially that is necessary to bring personalised and genetic treatments to the clinic, said Prof Pellegrini, who has written extensively on the challenges of translational advanced medicines (Attico E et al. Curr Transplant Rep. 2018; 5(3): 244–250. Pellegrini G et al. Stem Cells Transl Med. 2018;7(1):146–154). Because autologous treatments such as Holoclar use autologous cells from individual patients as raw materials, their contents are by definition far more diverse than in traditional medicines. This makes it difficult to apply the same kind of industrial process and increases quality controls usually required for regulatory approval – a significant hurdle to approval and commercialisation of stem cell and genetic therapies and a major reason for the extensive post-approval research EMA requires. Prof Pellegrini described the process by which Holoclar is produced as well as some of the quality checks required to ensure its safety and efficacy. It involves harvesting few stem cells from a spared area in one of the two eyes, so patients who have complete loss of stem cells in both eyes are not candidates. These harvested cells are cultured and expanded, and frozen as the raw material to produce one or more batches of the drug as required. Cells are thawed as drug substance, then cultured on a carrier from which a graft for transplant is constructed. The graft must be transplanted within 36 hours, and must be carefully handled within strict temperature limits in transport. Should the first graft fail a second can be produced, often from the original cell culture. Control samples are obtained and examined at the end of each phase of the process to monitor variability and select appropriate cell cultures to proceed, Prof Pellegrini noted. Tests can reveal cell abnormalities, or symmetric vs asymmetric division. The holoclone cells essential to the restoration process also can be identified by their level of p63 protein expression, and these must exceed 2.5% of the cultured cells to ensure efficacy. Post-transplant histology monitored in vivo integration of the transplanted tissues on the cornea, revealing restoration of normal corneal physiology over time. Prof Pellegrini also presented an update on a genetically modified stem cell treatment in development targeting a hereditary cause of LSCD, in the last treated case a life-threatening variant of junctional epidermolysis bullosa (JEB) that also produced burn-like lesions over 70% of the young patient’s body. Histological analysis found the genetically modified transplanted autologous stem cells integrated across the child’s epidermis over time. The result is a complete regeneration of the skin, and a return from near death in a burn unit to normal life three months after treatment (Hirsch T et al. Nature.2017; 10.1038/ nature24487) and up to three-to-five years. “This shows we can provide personalised medicine by genetic correction,” said Prof Pellegrini, of the Centre for Regenerative Medicine Stefano Ferrari, University of Modena and Reggio Emilia, Modena, Italy.