Posttransplant blockade of CXCR4 improves leukemia complete remission rates and donor stem cell engraftment without aggravating GVHD  

作　　者：Long Su Ming-Hui Fang Jun Zou Su-Jun Gao Xiao-Yi Gu Xian-Di Meng Xue Wang Zheng Hu Yong-Guang Yang 

机构地区：[1]Key Laboratory of Organ Regeneration&Transplantation of the Ministry of Education,The First Hospital,Jilin University,Changchun,China [2]National-Local Joint Engineering Laboratory of Animal Models for Human Diseases,Changchun,China [3]Department of Hematology,The First Hospital,Jilin University,Changchun,China [4]Department of Oncology,The First Hospital,Jilin University,Changchun,China [5]International Center of Future Science,Jilin University,Changchun,China

出　　处：《Cellular & Molecular Immunology》2021年第11期2541-2553,共13页中国免疫学杂志（英文版）

基　　金：This work was supported by grants from the NSFC(81941008,81870091 and 81900174);the Chinese Ministry of Education(IRT_15R24);The Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030303);the Chinese MOST(2017YFA0104402).

摘　　要：Allogeneic hematopoietic cell transplantation(allo-HCT)is a promising therapeutic option for hematological malignancies,but relapse resulting predominantly from residual disease in the bone marrow(BM)remains the major cause of treatment failure.Using immunodeficient mice grafted with laboratory-generated human B-ALL,our previous study suggested that leukemia cells within the BM are resistant to graft-versus-leukemia(GVL)effects and that mobilization with CXCR4 antagonists may dislodge leukemia cells from the BM,enabling them to be destroyed by GVL effects.In this study,we extended this approach to patient-derived xenograft(PDX)and murine T-ALL and AML models to determine its clinical relevance and effects on GVHD and donor hematopoietic engraftment.We found that posttransplant treatment with the CXCR4 antagonist AMD3100 significantly improved the eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients.AMD3100 also significantly improved GVL effects in murine T-ALL and AML models and promoted donor hematopoietic engraftment in mice following nonmyeloablative allo-HCT.Furthermore,posttransplant treatment with AMD3100 had no detectable deleterious effect related to acute or chronic GVHD.These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonists and allo-HCT.

关 键 词：LEUKEMIA allogeneic hematopoietic cell transplantation Graft-vs.-leukemia 

分 类 号：R730.5[医药卫生—肿瘤]