Abstract
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
Highlights
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL)
Lineage switch has been reported as a rare phenomenon, typically associated with poor prognosis[8,9,10,11], with myeloid leukaemia relapsing as lymphoid (T or B) lineage and vice versa[8,9,10,11,12,13,14,15,16,17,18,19]
Using genomic analysis of myeloid lineage switched leukaemias generated under CD19 CAR pressure and gene-editing techniques, we show this phenomenon is not due to alterations of CD19 but rather from a global reprograming of ALL with inherent lineage plasticity
Summary
ALL blast phenotypic alterations in patients post-CD19 CAR. Results from our trial CD19-CAR containing a CD28 costimulatory domain were previously reported, demonstrating excellent remission rates but relatively short in vivo persistence[27]. Complete remission induced in an infant with MLLrearranged ALL treated with a CD19 CAR containing a 41BB costimulatory domain with CAR persistence showed initial clearance of blasts with a relapse at day 30 with leukaemia that lost of B-cell markers, retained CD34 and HLA-DR, and gained of CD11b and CD33 expression (patient ALL_H0140, Fig. 1g,h). In contrast to E2a:PBX leukaemia, Em-RET pre-B cell ALL did not relapse following CD19 CAR via lineage switch suggesting that the occurrence of this resistance mechanism may depend on the genetic driver. The diverse gene expression profile of the post-CAR mixed phenotype and myeloid relapses derived from E2a:PBX1 ALL following CD19 CAR-T suggested emergence of leukaemia with distinct lineage characteristics resulted from reprogramming. E2a–PBX 38–1 E2a–D3 44–6 30–4 53–42 53–41 30–42 47–24 32–2 43–1 59–61 AYO1 24–6 25–2
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