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Therapeutic vaccination against leukaemia via the sustained release of co-encapsulated anti-PD-1 and a leukaemia-associated antigen

Nature Biomedical Engineering volume 5, pages 414–428 (2021)Cite this article

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Abstract

Therapeutic leukaemia vaccines have shown modest potency. Here, we show that the co-encapsulation of a leukaemia-associated epitope peptide highly expressed in leukaemia patients and of the immune checkpoint inhibitor anti-programmed-cell-death-protein-1 (anti-PD-1) in degradable poly(lactic acid) microcapsules resulted in the sustained release of the peptide and of the antibody, which led to the recruitment of activated antigen-presenting cells to the injection site, their uptake of the peptide and the transportation of the anti-PD-1 antibody to lymph nodes, enhancing the expansion of epitope-specific T cells and the activation of cytotoxic T cells. After single subcutaneous injections of vaccine formulations with different epitope peptides, mice bearing leukaemia xenografts derived from humanized cell lines or from primary cells from patients showed better therapeutic outcomes than mice receiving repeated injections of free antigen, antibody and a commercial adjuvant. The sustained release of a tumour-associated peptide and of anti-PD-1 may represent a generalizable strategy for boosting antitumour immune responses to leukaemia.

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Fig. 1: High expression of Eps8 and PD-1/PD-L1 in acute leukaemia.
Fig. 2: Preparation and characterization of self-healing microcapsules.
Fig. 3: APCs responses enhanced by coordination of sustained antigen release and APCs recruitment at the injection site.
Fig. 4: T-cell modulation and proliferation in the lymph nodes.
Fig. 5: Potent CTLs responses against leukaemia cells.
Fig. 6: In vivo anti-leukaemia effects in humanized Nalm6/Eps8+/PD-L1+-engrafted xenografts.
Fig. 7: Anti-leukaemic effects in humanized Molm-13/0201+/PD-L1+-engrafted xenografts.
Fig. 8: Potent anti-leukaemia activity in the PBMCs-PDX model.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding authors on reasonable request. The raw sequence data in Supplementary Fig. 4 are available at the BioProject database under accession number PRJNA639217.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 21821005 and 21622608), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB29040303), the National Key R&D Program of China (grant no. 2017YFA0207900), the Science and Technology Program of Guangzhou, China (grant no. 201704020216), the Natural Science Foundation of Guangdong Province, China (grant no. 2018B030311042), and the Guangzhou Regenerative Medicine and Health Guangdong Laboratory, China (grant no. 2018GZR110105014).

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  1. These authors contributed equally: Xiaoling Xie, Yuxing Hu, Tong Ye.

Authors and Affiliations

  1. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, P R China

    Xiaoling Xie, Yuxing Hu, Yiran Chen, Lijuan Zhou, Yanjie He & Yuhua Li

  2. State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, P R China

    Xiaoling Xie, Tong Ye, Feng Li, Xiaobo Xi, Shuang Wang, Xiaoyong Gao, Wei Wei & Guanghui Ma

  3. University of Chinese Academy of Sciences, Beijing, P R China

    Tong Ye, Feng Li, Xiaobo Xi, Wei Wei & Guanghui Ma

  4. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, P R China

    Yuhua Li

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Contributions

Y.L., G.M., W.W. and X.X. conceived and designed the study; X.X., Y.H., T.Y., Y.C. and L.Z. performed the experiments; T.Y. and X.X. helped to prepare the self-healing microcapsules and experimental assays. F.L., L.Z., S.W., Y.H. and X.G. facilitated the data and file processing. All authors discussed the results and commented on the manuscript. W.W. and X.X. wrote the initial manuscript. X.X., T.Y., Y.L., G.M. and W.W. further revised the manuscript.

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Correspondence to Wei Wei, Guanghui Ma or Yuhua Li.

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Xie, X., Hu, Y., Ye, T. et al. Therapeutic vaccination against leukaemia via the sustained release of co-encapsulated anti-PD-1 and a leukaemia-associated antigen. Nat Biomed Eng 5, 414–428 (2021). https://doi.org/10.1038/s41551-020-00624-6

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