Attenuated measles virus controls pediatric acute B-lineage lymphoblastic leukemia in NOD/SCID mice.
Novel therapies are needed for pediatric acute lymphoblastic leukemia resistant to conventional therapy. While emerging data suggest leukemias as possible targets of oncolytic attenuated measles virus, it is unknown whether measles virus can eradicate disseminated leukemia, in particular pediatric acute lymphoblastic leukemia. We evaluated the efficacy of attenuated measles virus against a large panel of pediatric xenografted and native primary acute lymphoblastic leukemias ex vivo, and against four different acute lymphoblastic leukemia xenografts of B-lineage in non-obese diabetic/severe combined immunodeficient mice. Ex vivo, attenuated measles virus readily spread among and effectively killed leukemia cells while sparing normal human blood cells and their progenitors. In immunodeficient mice with disseminated acute lymphoblastic leukemia a few intravenous injections of attenuated measles virus sufficed to eradicate leukemic blasts in the hematopoietic system and to control central nervous system disease resulting in long-term survival in three of the four xenografted B-lineage leukemias. Differential sensitivity of leukemia cells did not require increased expression of the measles entry receptors CD150 or CD46 nor absence of the anti-viral retinoic acid-inducible gene I/melanoma differentiation associated gene-5 /interferon pathway. Attenuated oncolytic measles virus is dramatically effective against pediatric B-lineage acute lymphoblastic leukemia in the pre-clinical setting warranting further investigations towards clinical translation.
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Nike C
NC
Lühl
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Felix
F
Zirngibl
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Carmen
C
Dorneburg
Laboratory of Biological Cancer Therapy, Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, China.
Jiwu
J
Wei
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Meike
M
Dahlhaus
Department of Pathology, University Medical Center Ulm, Germany.
Thomas F E
TF
Barth
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Lüder H
LH
Meyer
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Manon
M
Queudeville
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Sarah
S
Eckhoff
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.
Klaus-Michael
KM
Debatin
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany christian.beltinger@uniklinik-ulm.de.
Christian
C
Beltinger
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D008459:Measles virus / Q000235:genetics*; D051916:Membrane Cofactor Protein / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014158:Transcription, Genetic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D000097905:Roundabout Proteins
D015703:Antigens, CD; D051916:Membrane Cofactor Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C000604059:SLAMF1 protein, human