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-initiating in vivo clonogenic 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.

Liposomal Nanoparticles of a Spleen Tyrosine Kinase P-Site Inhibitor Amplify the Potency of Low Dose Total Body Irradiation Against Aggressive B-Precursor Leukemia and Yield Superior Survival Outcomes in Mice

“…NOD/SCID mice and CD22ΔE12 × BCR–ABL double-Tg mice with advanced leukemia were placed in autoclaved 2 L Pyrex Griffin glass beakers (VWR, Radnor, PA) and irradiated with single dose TBI (2 Gy for NOD/SCID mice/4 Gy for double-Tg C57BL/6 mice) delivered at 106 cGy/min using a self-shielded Cs-137 irradiator (Mark I Irradiator-68A, JL Sheperd & Associates, San Fernando, CA), as previously reported ( Uckun et al, 2015 ). Cells were irradiated with 2 Gy γ-rays in a single exposure using the Mark I Cs-137 irradiator ( Uckun et al, 2013 , Uckun et al, 2015a , Uckun et al, 2015 ).…”

Development of Polypeptide-based Nanoparticles for Non-viral Delivery of CD22 RNA Trans-splicing Molecule as a New Precision Medicine Candidate Against B-lineage ALL

“…The research was approved by the IACUC of CHLA. Our standard animal care procedures were previously reported ( Uckun et al, 2015d , Uckun et al, 2015e ). In 2 independent experiments, we examined the effects of CD22-RTM on the leukemia-initiating cells of the xenograft clones.…”

Value of Liberal Arts education in the Era of Precision Medicine

“…Data mining, bioinformatics, computational modeling and simulation have increasingly become integral to development of novel hypotheses in disease progression and potentially novel therapeutic innovations that target prominent receptors in leukemias (CD19 and CD22 receptors) to eradicate cancer cells. [14][15][16][17][18][19][20] Our project attempted to link data mining efforts that identify genetic signatures in high risk patient sub-groups to data explorations methods developed using R made available in Bioconductor (http://www.bioconductor. org/) by writing interactive, exploration based statistical analysis platform provided by Shiny applications (http://shiny.rstudio.com/).…”