Ex vivo and in vivo complex drug combination analysis for improved efficacy and specificity in high-risk childhood acute lymphoblastic leukaemia

Childhood acute lymphoblastic leukaemia responds to standard treatment, but more targeted drugs are needed. Patient-derived xenografts (PDX) more closely resemble patient cancers than cell lines. PDXs do not proliferate well ex vivo without mesenchymal stromal cells (MSC). High-content microscopy allows separation of the cell types to allow greater accuracy to filter down the best drug combinations, and may provide insight into patient drug responses observed in the clinic. PDX-MSC cells were analysed with combinations of targeted and chemotherapeutic agents in an ex vivo co-culture system with some combinations deemed to be particularly effective. Caspase assays demonstrated increased cell death when drugs were used in combination in PDXs with high-risk cytogenetics. Subsequent in vivo testing revealed a triple combination was required in order to decrease leukaemic burden of very high risk subtypes, though ultimately resistance to the combination was still observed. Analysis of triple combination treated samples retrieved from mice revealed complete resistance to only one of the three drugs, suggesting resistance could be transient, or related to the pharmacokinetics of the drug.

Publication History

Article published online:
17 May 2022