Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia.

Sonali P Barwe,John Muth,Ezio Bonvini,Edward Anders Kolb,Jan Davidson-Moncada,Anilkumar Gopalakrishnapillai,Anne Kisielewski

doi:10.3390/jcm11051333

Abstract

Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 × CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.

Highlights

Children with acute myeloid leukemia (AML) suffer a poor prognosis, even though highly intensive chemotherapy is used for their treatment
CD123 expression on the cell surface was evaluated in a panel of pediatric AML patient-derived xenograft (PDX) lines generated in the laboratory (Table S1)
Consistent with previous reports [4], we observed that CD123 was expressed on the cell surface of the majority of pediatric AML samples according to a monomodal distribution (Figure 1A)

Summary

Introduction

Children with acute myeloid leukemia (AML) suffer a poor prognosis, even though highly intensive chemotherapy is used for their treatment. A third of children with newly diagnosed AML and all children following disease relapse require myeloablative therapy with hematopoietic stem cell transplantation [1,2]. In order to improve outcomes, we must focus on the development and application of targeted therapies that can replace the significantly toxic standard-of-care. Cell-surface CD123 (IL3RA) is expressed in most AML samples, with increased expression in poor-prognosis tumors [3–7]. CD123 is a high-priority target for new therapy development in children [8,9]. A systematic analysis of CD123 expression levels in several pediatric AML patients revealed an association of higher CD123 expression with inferior clinical outcome and the presence of high-risk genetic aberrations, such as KMT2A rearrangements and FLT3-internal tandem duplications [4,5]

Methods

Results

Conclusion