title: Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-Resistant B-Precursor Acute Lymphoblastic Leukemia in Mice.
abstract: In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high "minimal residual disease" (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand × soluble TRAIL ("CD19L-sTRAIL") fusion protein. CD19L-sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiatingin vivoclonogenic fraction. Low dose total body irradiation (TBI) combined with CD19L-sTRAIL was highly effective against (1) xenografted CD19+radiochemotherapy-resistant human BPL in NOD/SCID (NS) mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2) radiation-resistant advanced stage CD19+murine BPL with lymphomatous features in CD22ΔE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT.
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027 ; Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027 ; Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027.
authors.forename: Dorothea E
authors.initials: DE
authors.lastname: Myers
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Rose Pathology Services, LLC, St. Paul, MN 55104.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rose
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027 ; Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082, USA.
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
keywords: Bone marrow transplantation; Leukemia; cancer; personalized medicine; precision medicine; radiation resistance; total body irradiation