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首页> 外文期刊>EBioMedicine >Low Dose Total Body Irradiation Combined With Recombinant CD19-LigandxSoluble TRAIL Fusion Protein is Highly Effective Against Radiation-resistant B-precursor Acute Lymphoblastic Leukemia in Mice
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Low Dose Total Body Irradiation Combined With Recombinant CD19-LigandxSoluble TRAIL Fusion Protein is Highly Effective Against Radiation-resistant B-precursor Acute Lymphoblastic Leukemia in Mice

机译：低剂量全身照射结合重组CD19-Ligandx可溶性TRAIL融合蛋白对小鼠的抗辐射B前体急性淋巴细胞白血病具有高度有效的作用

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In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after the 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-Ligandxsoluble 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 CD22@DE12xBCR-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.
机译：在高风险缓解的B前体急性淋巴细胞白血病（BPL）患者中，即使在使用非常密集的全身照射（TBI）为基础的调节方案后，造血干细胞移植（HSCT）后的复发率仍然很高，尤其是在高“最小残留疾病”（MRD）负担的患者。因此，迫切需要能够杀死抗辐射的BPL细胞并选择性增强其辐射敏感性的新试剂。我们报告了临床前的原则证明，可以通过将放射线与重组人CD19-Ligandx可溶性TRAIL（“ CD19L-sTRAIL”）融合蛋白相结合来增强针对BPL的放射疗法的效力。 CD19L-sTRAIL持续杀死来自BPL患者的抗辐射原发性白血病细胞以及BPL异种移植细胞及其引发白血病的体内克隆性成分。低剂量全身照射（TBI）与CD19L-sTRAIL结合可有效抵抗（1）NOD / SCID（NS）小鼠中异种移植的抗CD19 ^ +放射化学治疗的人BPL，这些小鼠受到了致命剂量的复发性异种移植细胞的攻击BPL患者以及（22）在CD22 @ DE12xBCR-ABL双转基因小鼠中具有淋巴瘤特征的抗辐射晚期CD19 ^ +小鼠BPL。我们假设将CD19L-sTRAIL纳入高风险BPL患者的移植前TBI方案将改善HSCT后的生存结局。

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