Targeting pediatric leukemia propagating cells using anti-CD200 antibody therapy.

Abstract

Treating refractory pediatric acute lymphoblastic leukemia (ALL) remains a challenge despite impressive remission rates (>90%) achieved in the last decade. The use of innovative immunotherapeutic approaches, such as anti-CD19 chimeric antigen receptor T cells does not ensure durable remissions, as cells with leukemia propagating ability (LPC) that lack expression of CD19 can cause relapse, signifying the need to identify new markers of ALL. Here we investigated expression of CD58, CD97 and CD200, previously shown to be overexpressed in B cell precursor (BCP) ALL, in CD34+/CD19+, CD34+/CD19-, CD34-/CD19+ and CD34-/CD19- LPC to assess their potential as therapeutic targets. Whole genome microarray and flow cytometric analyses showed significant overexpression of these molecules compared to normal controls. CD58 and CD97 were mainly co-expressed with CD19 and were not prerequisite for leukemia engraftment in immune deficient mice. In contrast, expression of CD200 was essential for engraftment and serial transplantation of cells in measurable residual disease (MRD) low risk cases. Moreover, these CD200+ LPC could be targeted using the monoclonal antibody, TTI-CD200, in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low risk ALL, with minimal off tumour effects that beset current immunotherapeutic approaches.