Potent preclinical activities of CD9 antibodies against high-risk pediatric B-precursor acute lymphoblastic leukemia
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摘要Background:
B-precursor acute lymphoblastic leukemia (B-ALL) is the most common malignancy and the leading cause of cancer-related death in children. Despite advances in risk-adapted multi-agent chemotherapy, specific subtypes of high-risk and relapsed/refractory B-ALL are still associated with dismal outcomes, underscoring the need for development of novel and effective therapeutic strategies.

Aims:
CD9, a tetraspanin family protein, regulates multiple physiologic processes and has been associated with metastasis and disease progression in various types of cancers. We recently reported that CD9 expression was associated with inferior 5-year overall and relapse-free survival in a cohort of pediatric B-ALL patients (Leung et al, EHA 2017). In this study, we aim to comprehensively evaluate the preclinical efficacy and mechanisms of targeting CD9 with neutralizing antibodies as a new treatment strategy for childhood B-ALL.

Methods:
NOD/SCID mice were transplanted with patient-derived B-ALL blasts or cell lines, and randomized to receive CD9 antibody or IgG control, in addition to conventional chemotherapy consisting of vincristine, dexamethasone and L-asparaginase. Leukemic burden was assessed by bioluminescence imaging or flow cytometric identification of human CD45+CD19+ cells in murine bone marrow, spleen, blood and liver. Animals transplanted with cord blood CD34+ cells were used to evaluate the effect of CD9 antibody on normal hematopoiesis. Leukemic cell proliferation and apoptosis were measured in cultures with or without bone marrow stroma by Trypan blue exclusion and Annexin V-7AAD staining, respectively. Co-immunoprecipitation assay was performed in B-ALL cell lines to identify CD9-binding proteins.

Results:
Administration of CD9 antibody as a single agent substantially reduced multi-organ leukemic burden by >90% and significantly prolonged survival of animals xenografted with the intermediate-risk TCF3-PBX1+ 697 and high-risk MLL-AF4+ RS4;11, but not the standard-risk ETV6-RUNX1+ Reh cell lines. In addition, CD9 blockade effectively suppressed disease progression of patient-derived xenografts of high-risk and relapsed/refractory B-ALL with distinct cytogenetic features, including MLL-rearrangements, TCF3-HLF translocation and hypodiploidy. We also showed that CD9 antibody did not affect overall and multilineage engraftment of cord blood hematopoietic stem cells, which could be attributed to low expression of CD9 in the primitive CD34+CD38- subpopulation. Combining CD9 antibody with conventional chemotherapy further reduced leukemic burden and prolonged animal survival, when compared with animals treated with CD9 antibody or chemotherapy alone. In vitro, CD9 blockade significantly decreased proliferation of leukemic cells and enhanced vincristine-, dexamethasone- and L-asparaginase-induced apoptosis in both mono- and stromal co-cultures. Mechanistic studies revealed that CD9 was functionally involved in leukemia-stroma interaction through binding and modulating the affinity of integrin very late antigen-4.

Conclusion:
Our results collectively suggest that CD9 blockade, in adjunct to chemotherapy, could be a novel and promising strategy for treatment of high-risk and relapsed/refractory pediatric B-ALL, possibly mediated by disruption of leukemia-stroma interaction in the bone marrow microenvironment.
著者Kam Tong Leung, Chi Zhang, Kathy Yuen Yee Chan, John Tak Kit Cheung, Karen Li, Chi Kong Li
會議名稱23rd Congress of European Hematology Association
會議開始日14.06.2018
會議完結日17.06.2018
會議地點Stockholm
會議國家/地區瑞典
出版年份2018
語言美式英語

上次更新時間 2018-09-10 於 11:40