Understanding lineage switching in haematopoietic malignancies as a mechanism of resistance to CAR-T therapy

Acute lymphoblastic leukaemia (ALL) is the most common cause of cancer related mortality in children and young adults. Although outcomes have improved significantly a substantial number of patients are either refractory to initial therapy or relapse after achieving a clinical remission. Long term survival in these patients is very poor and, in this context, chimeric antigen receptor (CAR) T-cell therapy directed against CD19 has emerged as a major avenue to cure these children and young adults. Unfortunately, however, resistance to CAR-T therapy can also emerge through a remarkable process of lineage switching from a lymphoid to a myeloid malignancy that no longer expresses CD19.

The goal of this PhD project is to develop sophisticated models that would allow us to investigate lineage switching and CD19 epitope loss both in vitro and in vivo. Ultimately the ambition of the project is to identify novel therapeutic strategies that prevent this form of therapeutic escape from CAR-T therapy.

Supervisors:
Prof Mark Dawson, Peter MacCallum Cancer Centre, The University of Melbourne

Prof Tim Somervaille, The University of Manchester