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A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia

Nature Biomedical Engineering volume 4, pages 40–51 (2020)Cite this article

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Abstract

Acute myeloid leukaemia (AML) is a malignancy of haematopoietic origin that has limited therapeutic options. The standard-of-care cytoreductive chemotherapy depletes AML cells to induce remission, but is infrequently curative. An immunosuppressive AML microenvironment in the bone marrow and the paucity of suitable immunotherapy targets limit the induction of effective immune responses. Here, in mouse models of AML, we show that a macroporous-biomaterial vaccine that delivers the cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF), the Toll-like-receptor-9 agonist cytosine–guanosine oligodeoxynucleotide and one or multiple leukaemia antigens (in the form of a defined peptide antigen, cell lysates or antigens sourced from AML cells recruited in vivo) induces local immune-cell infiltration and activated dendritic cells, evoking a potent anti-AML response. The biomaterial-based vaccine prevented the engraftment of AML cells when administered as a prophylactic and when combined with chemotherapy, and eradicated established AML even in the absence of a defined vaccine antigen. Biomaterial-based AML vaccination can induce potent immune responses, deplete AML cells and prevent disease relapse.

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Fig. 1: PEG-alginate-based cryogel vaccine sustains release of cytokine and adjuvant in vitro, and preferentially concentrates and activates antigen-presenting cells in vivo.
Fig. 2: Prophylactic immunization with bone marrow lysate or WT1 peptide prevents AML engraftment.
Fig. 3: Secondary transplants indicate the absence of residual AML cells and the transfer of immunity into transplant recipients.
Fig. 4: iCt induces immunogenic cell death in vitro and combination of iCt and cryogel vaccination with WT1 depletes established AML.
Fig. 5: Combination of iCt with antigen-free vaccination debulks AML, depletes Treg cells and enhances antigen-specific T cells.
Fig. 6: Secondary transplants indicate the absence of residual AML cells and the transference of immunity into transplant recipients.

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Data availability

All data supporting the results of this study are provided with the in the Article and its Supplementary Information. Raw datasets are available at https://doi.org/10.7910/DVN/44ARAC.

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Acknowledgements

We thank M. Brennan, A. Spielmann, M. Sobral, M. Dellacherie and H. Wang for technical assistance. The work was supported by the National Institutes of Health through grants R01CA223255, R01EB023287, U19HL129903 and U01CA214369. N.J.S. received support from the Cancer Research Institute through the CRI Irvington Postdoctoral Fellowship. A.J.N. acknowledges a Graduate Research Fellowship from the National Science Foundation.

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Author notes

  1. Nisarg J. Shah

    Present address: Department of Nanoengineering, Programs in Chemical Engineering and Immunology, University of California, San Diego, La Jolla, CA, USA

  2. These authors contributed equally: Nisarg J. Shah, Alexander J. Najibi.

Authors and Affiliations

  1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Nisarg J. Shah, Alexander J. Najibi, Ting-Yu Shih, Angelo S. Mao & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA

    Nisarg J. Shah, Alexander J. Najibi, Ting-Yu Shih, Angelo S. Mao & David J. Mooney

  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    Nisarg J. Shah, Azeem Sharda & David T. Scadden

  4. Harvard Stem Cell Institute, Cambridge, MA, USA

    Nisarg J. Shah, Azeem Sharda & David T. Scadden

  5. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA

    David T. Scadden

  6. Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    David T. Scadden

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Contributions

N.J.S., A.J.N., T.-Y.S., A.S.M., D.T.S. and D.J.M. designed the experiments. N.J.S., A.J.N., T.-Y.S., A.S.M. and A.S. conducted experiments and analysed data. N.J.S., A.J.N., D.T.S and D.J.M. wrote the manuscript.

Corresponding authors

Correspondence to David T. Scadden or David J. Mooney.

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Competing interests

Magenta Therapeutics, director, equity and consulting: D.T.S.; Agios Pharmaceuticals, director, equity: D.T.S.; Fate Therapeutics, equity and consulting: D.T.S.; Clear Creek Bio, director, equity and consulting: D.T.S.; FOG Pharma, consulting: D.T.S.; Red Oak Medicines, director, equity and consulting: D.T.S.; Lifevaultbio, director, equity: D.T.S.; Bone Therapeutics, consulting: D.T.S.; Indee Labs, consulting: A.J.N.; Novartis, sponsored research: D.T.S and D.J.M.; Agnovos, consulting: D.J.M.; Amgen, sponsored research: D.J.M.; Samyang Corp., consulting: D.J.M.; Decibel, sponsored research: D.J.M.; Merck, sponsored research: D.J.M.; Immulus, equity: D.J.M.; Inventors, patent applications: N.J.S., A.J.N., A.S.M., T.-Y.S., D.J.M. and D.T.S.

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Shah, N.J., Najibi, A.J., Shih, TY. et al. A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia. Nat Biomed Eng 4, 40–51 (2020). https://doi.org/10.1038/s41551-019-0503-3

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