Preclinical study of a combined phenotype/genotype targeted treatment approach toward Ph-like acute lymphoblastic leukemia

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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like or BCR-ABL-like ALL) is a distinct high-risk subtype of ALL that was initially identified by a gene expression signature similar to Ph+ ALL in the absence of a BCR-ABL rearrangement. Fusion genes involving various cytokine receptors or tyrosine kinases have been identified which can be broadly subdivided into JAK- and ABL- class alterations. The prevalence of Ph-like ALL is age dependent and varies from 10% at childhood to almost 30% in adults. Importantly, Ph-like NCI high-risk ALL is associated with a poor prognosis requiring intensified chemotherapy and/or hematopoietic stem cell transplantation. To advance treatment options of Ph-like ALL a combined natural killer cell immunotherapy and tyrosine kinase inhibition (TKI) approach is being proposed. Research will focus on biology-driven optimization of NK cell functionality in the context of tyrosine kinase inhibition. To this end, we will generate induced pluripotent stem cell (iPSC)-derived NK cells endowed with a CD19-directed chimeric antigen receptor and NK cell signaling domains. To prevent immune cell exhaustion and enhance functionality of iPSC-NK cells an adaptive or memory-like state will be induced by interleukin (IL) -driven pre-activation, expression of transactivating ARID5B, or CRISPR-mediated deletion of the IL-signaling checkpoint CISH. Metabolic and epigenetic state of adaptive versus canonical iPSC-CAR-NK cells will be determined. In particular, the impact of TKI on CAR activity will be evaluated. We have established a variety of PDX Ph-like ALL models representing ABL- or JAK-class kinase aberrations which will be utilized for in vivo application of iPSC-CAR-NK cells in the presence versus absence of TKI. Taken together, the knowledge generated by the research proposed herein could provide valuable clues as to how to integrate cellular immunotherapy and mutation-targeted precision medicine in cancer treatment.