ADVANCES IN HAEMATOPOIETIC STEM CELL THERAPY INCLUDING CORD BLOOD AND STEM CELL GENE THERAPY

Abstract

Allogeneic haematopoietic stem cell transplant (HSCT) is used in the paediatric setting to treat a wide range of malignant and non-malignant diseases including myeloid malignancy and metabolic lysosomal storage disorders (LSDs). The risks of the procedure must be balanced against the risks of the underlying diseases and conservative management. Current approaches are limited by the morbidity and mortality associated with allogeneic HSCT as well as other issues relating to the underlying condition. These include relapse in myeloid malignancy, which remains the leading cause of treatment failure, whereas insufficient enzyme delivery to control disease manifestations is a major problem affecting transplant efficacy in LSDs. We explored new strategies to mitigate these limitations including T-replete cord blood transplant for paediatric myeloid malignancy and autologous haematopoietic stem cell gene therapy (HSCGT) for LSDs. T-replete cord blood transplant results in reduced relapse and improved event free survival in children with myeloid malignancy compared with other donor sources and this effect is particularly striking for children going into transplant with evidence of residual disease. Autologous HSCGT is feasible in infants as small as 5kg and is associated with reduced morbidity and mortality compared with allogeneic HSCT. Furthermore, gene addition using lentiviral vectors is both safe and can be exploited to achieve supraphysiological enzyme levels in the recipient, thereby addressing disease manifestations not amenable to allogeneic HSCT. T-replete cord blood transplant and autologous HSCGT for LSDs provide promising solutions to address current unmet needs within the field of paediatric allogeneic HSCT and are likely to play a key role in the evolving field of paediatric cellular therapy over the coming years.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Brian Bigger (Supervisor) & Robert Wynn (Supervisor)