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B cell acute lymphoblastic leukemia relapse following CD19 CAR immune-pressure via de-differentiation and lineage switch

Thursday, September 17, 2015 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace
NCI
CANCER-9

* FARE Award Winner

Authors

  • E Jacoby
  • H Qin
  • S Nguyen
  • Y Yang
  • CD Chien
  • K Welp
  • J Shern
  • TJ Fry

Abstract

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.

Category: Cancer Biology