5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox

Author:

Müller, Fabian

Cunningham, Tyler

Stookey, Stephanie

Tai, Chin-Hsien

Burkett, Sandra

Jailwala, Parthav

Stetler Stevenson, Maryalice

Cam, Margaret C

Wayne, Alan S

Pastan, Ira
Author Address

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Department of Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702., Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702., Collaborative Bioinformatics Resource , Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Children 39;s Center for Cancer and Blood Diseases, Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children 39;s Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027., Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; pastani@mail.nih.gov.,

1. Year: 2018
2. Date: Feb 20
3. Epub Date: 2018 02 05
Journal: Proceedings of the National Academy of Sciences of the United States of America
1. Volume: 115
2. Issue: 8
3. Pages: E1867-E1875
Type of Article: Article

Abstract:

Moxetumomab pasudotox (Moxe) is a chimeric protein composed of an anti-CD22 Fv fused to a portion ofPseudomonasexotoxin A and kills CD22-expressing leukemia cells. It is very active in hairy-cell leukemia, but many children with relapsed/refractory acute lymphoblastic leukemia (ALL) either respond transiently or are initially resistant. Resistance to Moxe in cultured cells is due to low expression of diphthamide genes (DPH), but only two of six ALL blast samples from resistant patients had low DPH expression. To develop a more clinically relevant model of resistance, we treated NSG mice bearing KOPN-8 or Reh cells with Moxe. More than 99.9% of the cancer cells were killed by Moxe, but relapse occurred from discrete bone marrow sites. The resistant cells would no longer grow in cell culture and showed major chromosomal changes and changes in phenotype with greatly decreased CD22. RNA deep sequencing of resistant KOPN-8 blasts revealed global changes in gene expression, indicating dedifferentiation toward less-mature B cell precursors, and showed an up-regulation of myeloid genes. When Moxe was combined with 5-azacytidine, resistance was prevented and survival increased to over 5 months in the KOPN-8 model and greatly improved in the Reh model. We conclude that Moxe resistance in mice is due to a new mechanism that could not be observed using cultured cells and is prevented by treatment with 5-azacytidine.

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