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Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia.
Journal article

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia.

  • McGinn OJ Immunology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.
  • Krishnan S Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.
  • Bourquin JP Division of Oncology & Children's Research Center, University Children's Hospital, University of Zurich, Switzerland.
  • Sapra P Pfizer Inc. Pearl River, NY10965-1299, USA.
  • Dempsey C Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.
  • Saha V Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK Peter.Stern@cruk.manchester.ac.uk vaskar.saha@tmckolkata.com.
  • Stern PL Immunology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK Peter.Stern@cruk.manchester.ac.uk vaskar.saha@tmckolkata.com.
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  • 2017-03-26
Published in:
  • Haematologica. - 2017
Animals
Antibodies, Monoclonal, Humanized
Antigens, Neoplasm
Antineoplastic Combined Chemotherapy Protocols
Bone Marrow
Cell Movement
Dexamethasone
Heterografts
Humans
Mice
Molecular Targeted Therapy
Neoplasm, Residual
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Prognosis
English Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/90882
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