Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia.
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-scidIL2Rγnullmouse xenograft barrier, migratedin vitroon a CXCL12 gradient, preferentially localized to bone marrowin vivoand 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-scidIL2Rγnullmice. 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.
Immunology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.
Owen J
OJ
McGinn
Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.|Tata Translational Cancer Research Center, Tata Medical Center, Kolkata, India.
Shekhar
S
Krishnan
Division of Oncology & Children's Research Center, University Children's Hospital, University of Zurich, Switzerland.
Jean-Pierre
JP
Bourquin
Pfizer Inc. Pearl River, NY10965-1299, USA.
Puja
P
Sapra
Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK.
Clare
C
Dempsey
Paediatric Oncology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK Peter.Stern@cruk.manchester.ac.uk vaskar.saha@tmckolkata.com.|Tata Translational Cancer Research Center, Tata Medical Center, Kolkata, India.
Vaskar
V
Saha
Immunology, Division of Molecular & Clinical Cancer Sciences, University of Manchester, UK Peter.Stern@cruk.manchester.ac.uk vaskar.saha@tmckolkata.com.
Peter L
PL
Stern
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000032:analysis / Q000187:drug effects* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow; D002465:Cell Movement; D003907:Dexamethasone / Q000627:therapeutic use; D064593:Heterografts / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D018365:Neoplasm, Residual / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology; D011379:Prognosis
C581920:A1mcMMAF; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; C031192:oncofetal antigens; D003907:Dexamethasone