NIH Research Festival
FARE Award Winner
Novel treatments for acute lymphoblastic leukemia (ALL) are utilizing the patient’s T cells targeting surface molecules on the leukemic blasts. CD19 is a surface marker restricted to B cells and highly expressed on B cell ALL. CD19 has been targeted through genetically engineered chimeric-antigen receptor (CAR) T cells, and via bispecific CD3-CD19 antibodies, with reports of relapse via CD19 loss. We used a murine injectable pre-B ALL driven by an E2a:PBX transgene, which results in death of recipients within 21 days. Murine CD19 CAR treatment of ALL-bearing mice resulted in long-term remission with long persistence of T cells. However, late relapses occurred essentially in all CAR treated animals when followed up to 1 year, all with loss of CD19 expression, compatible with clinical reports. Relatively early relapses had a pre-B phenotype with isolated loss of CD19 but retained expression of B220, CD22 and CD127. Later relapses had loss of all the B cell surface markers, along with down regulation of B cell transcripts (such as EBF1 and PAX5) in the mRNA. These late relapses showed expression of cell surface markers compatible with a myeloid lineage (Gr1, Mac1), T cell or undifferentiated lineage (KIT, CD9), confirmed by RNA-sequencing. Isolated loss of CD19 was reversible upon in-vivo passage of leukemia, but lineage switch patterns were stable in-vivo. Our data demonstrates plasticity of leukemic cells under antigen-specific immune pressure, with de-differentiation and lineage switch. This novel escape mechanism is already seen in clinical trials.
Scientific Focus Area: Cancer Biology
This page was last updated on Friday, March 26, 2021