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

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Abstract

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.

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Acknowledgements

We would like to thank Mr. Zhan-Wei Sun and Mrs. Guang-Jie Sun for their excellent animal care and Mr. Li-Qun Wang for patient sample collection. 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), and the Chinese MOST (2017YFA0104402).

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Authors and Affiliations

  1. Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital, Jilin University, Changchun, China

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

  2. National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China

    Long Su, Ming-Hui Fang, Jun Zou, Xian-Di Meng, Xue Wang, Zheng Hu & Yong-Guang Yang

  3. Department of Hematology, The First Hospital, Jilin University, Changchun, China

    Long Su & Su-Jun Gao

  4. Department of Oncology, The First Hospital, Jilin University, Changchun, China

    Xiao-Yi Gu

  5. International Center of Future Science, Jilin University, Changchun, China

    Yong-Guang Yang

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  1. Long Su
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  2. Ming-Hui Fang
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  3. Jun Zou
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  8. Zheng Hu
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Contributions

Conceptualization: LS, ZH, Y-GY; Methodology: LS, M-HF, JZ, S-JG, X-YG, ZH, Y-GY; Investigation: LS, M-HF, JZ, S-JG, X-YG, X-DM, XW; Visualization: LS, X-YG, XW; Funding acquisition: LS, ZH, Y-GY; Project administration: LS, ZH, Y-GY; Supervision: ZH, Y-GY; Writing—original draft: LS, ZH, Y-GY; Writing—review & editing: all authors.

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Correspondence to Zheng Hu or Yong-Guang Yang.

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Su, L., Fang, MH., Zou, J. et al. Posttransplant blockade of CXCR4 improves leukemia complete remission rates and donor stem cell engraftment without aggravating GVHD. Cell Mol Immunol 18, 2541–2553 (2021). https://doi.org/10.1038/s41423-021-00775-9

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