Allogeneic stem cell transplantation represents a widely-used treatment for children with acute leukaemia in first complete remission but carrying high risk features predicting the occurrence of relapse. It is also routinely employed to rescue patients who fail conventional therapy. Unfortunately, not all patients have an actually identical, either related or an unrelated, donor and for these patients novel approaches of T-cell depleted haploidentical transplant using either the father or the mother of the patient have been developed. Through the selective depletion of alpha/beta T-lymphocytes we have been able to document a good prevention of graft versus host disease and a remarkable leukaemia free survival as published in two papers in Blood, one last year and one a few weeks ago. But when we look at the immune reconstitution of these patients we found that there was room for improving the recovery of adaptive immunity and to address this issue we decided to invest in a novel and original approach based on the infusion of a titrated number of donor T-cells which have been genetically modified to the transduction with a safety switch or, if you prefer, a suicide gene.
Through this approach you can infuse these donor T-cells and in case of the occurrence of severe GVHD, or GVHD not responding to conventional therapy, you can activate the suicide gene with a prompt elimination of these genetically modified T-cells and resolution of GVHD signs and symptoms.

In a multicentre study that we have conducted, both in Europe and in the US, which recruited 100 children with either acute lymphoblastic or acute myeloid leukaemia we have been able to demonstrate a very good outcome of the patient with a low risk of transplant related mortality in the order of 3% and a risk of recurrence in the order of 15%. This means that these patients at three years from the allograft had a probability of disease free survival above 80%, this failure being more than competitive with the results that one can obtain using either an actually identical sibling or an unrelated volunteer donor.

What are the implications for this research?

The implication is that now paediatricians have a new transplant option to be offered to the patients in need of an allograft and this will allow us to transplant almost all patients that need to receive this type of procedure. The other relevant implication is that through this approach the incidence of immune-mediated complications, namely either acute or chronic graft versus host disease, will be particularly low, this translating into a benefit on the long-term quality of life of surviving patients.