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Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy

Nature Biomedical Engineering volume 2, pages 831–840 (2018)Cite this article

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Abstract

Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC–platelet–aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade.

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Fig. 1: Characterization of the S–P–aPD-1 cellular combination delivery system.
Fig. 2: In vivo treatment efficacy of S–P–aPD-1.
Fig. 3: Analysis of T cells, cytokines and chemokines.
Fig. 4: S–P–aPD-1 induced a durable immune response.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Source data for the figures are available in Figshare at https://doi.org/10.6084/m9.figshare.7033481.

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Acknowledgements

This work was supported by grants from the start-up packages of UNC/NC State and UCLA, the Sloan Research Fellowship of the Alfred P. Sloan Foundation, the National Key R&D Program of China (2017YFA0205600), the National Natural Science Foundation of China (51728301, 81690263) and the China Scholarship Council (CSC). We acknowledge B. Blazar at the University of Minnesota for providing the C1498-Luc cell line and M. Liu at New York University for assistance in cytokine analysis. Z.G. acknowledges support from W. Gu and P. Zhang.

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Authors and Affiliations

  1. Department of Bioengineering, University of California, Los Angeles, CA, USA

    Quanyin Hu, Wujin Sun, Jinqiang Wang, Huitong Ruan, Xudong Zhang & Zhen Gu

  2. California NanoSystems Institute, University of California, Los Angeles, CA, USA

    Quanyin Hu, Wujin Sun, Jinqiang Wang, Huitong Ruan, Xudong Zhang & Zhen Gu

  3. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA

    Quanyin Hu, Jinqiang Wang, Huitong Ruan, Yanqi Ye, Chao Wang, Ke Cheng & Zhen Gu

  4. Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai, China

    Huitong Ruan & Weiyue Lu

  5. National Engineering Research Center for Tissue Restoration and Reconstruction, and School of Biomedical Science and Engineering, South China University of Technology, Guangzhou, China

    Song Shen & Jun Wang

  6. Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA

    Ke Cheng

  7. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Gianpietro Dotti & Joshua F. Zeidner

  8. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA

    Zhen Gu

  9. Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, USA

    Zhen Gu

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Contributions

Q.H. and Z.G. designed the experiments. Q.H., W.S., J.W., H.R., Y.Y., X.Z. and C.W. performed the experiments and collected the data. All authors contributed to writing the manuscript, discussing the results and implications, and editing the manuscript at all stages.

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Correspondence to Zhen Gu.

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Competing interests

Patents describing the cell-combination drug-delivery system documented in this article have been filed with the US Patent Office. Q.H. and Z.G. are inventors of the following provisional patent application: US 62/653,843. J.F.Z. has received honoraria from Agios, Celgene and Tolero, consultancy from Celgene and Asystbio Laboratories, and research funding from Merck, Takeda and Tolero. The other authors declare no competing interests.

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Hu, Q., Sun, W., Wang, J. et al. Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy. Nat Biomed Eng 2, 831–840 (2018). https://doi.org/10.1038/s41551-018-0310-2

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