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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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.
Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).
Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 4, 149RA118 (2012).
Yates, J. W., Wallace, H. J. Jr., Ellison, R. R. & Holland, J. F. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother. Rep. 57, 485–488 (1973).
Tallman, M. S., Gilliland, D. G. & Rowe, J. M. Drug therapy for acute myeloid leukemia. Blood 106, 1154–1163 (2005).
Barrett, A. & Le Blanc, K. Immunotherapy prospects for acute myeloid leukaemia. Clin. Exp. Immunol. 161, 223–232 (2010).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2006).
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).
Horowitz, M. M. et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).
Li, H. W. & Sykes, M. Emerging concepts in haematopoietic cell transplantation. Nat. Rev. Immunol. 12, 403–416 (2012).
Cummins, K. D. & Gill, S. Chimeric antigen receptor T-cell therapy for acute myeloid leukemia: how close to reality? Haematologica 104, 1302–1308 (2019).
Chapuis, A. G. et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat. Med. 25, 1064–1072 (2019).
Anguille, S., Van Tendeloo, V. F. & Berneman, Z. N. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia 26, 2186–2196 (2012).
Grosso, D. A., Hess, R. C. & Weiss, M. A. Immunotherapy in acute myeloid leukemia. Cancer 121, 2689–2704 (2015).
Oka, Y. et al. Cancer immunotherapy targeting Wilms’ tumor gene WT1 product. J. Immunol. 164, 1873–1880 (2000).
Rosenfeld, C., Cheever, M. & Gaiger, A. WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Leukemia 17, 1301–1312 (2003).
Maslak, P. G. et al. Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv. 2, 224–234 (2018).
Rezvani, K. et al. Leukemia-associated antigen-specific T cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 111, 236–242 (2008).
Irvine, D. J. Materializing the future of vaccines and immunotherapy. Nat. Rev. Mater. 1, 15008 (2016).
Gu, L. & Mooney, D. J. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat. Rev. Cancer 16, 56–66 (2016).
Zakrzewski, J. L., Van Den Brink, M. R. & Hubbell, J. A. Overcoming immunological barriers in regenerative medicine. Nat. Biotechnol. 32, 786–794 (2014).
Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016).
Leleux, J. & Roy, K. Micro and nanoparticle‐based delivery systems for vaccine immunotherapy: an immunological and materials perspective. Adv. Healthc. Mater. 2, 72–94 (2013).
Rudra, J. S., Tian, Y. F., Jung, J. P. & Collier, J. H. A self-assembling peptide acting as an immune adjuvant. Proc. Natl Acad. Sci. USA 107, 622–627 (2010).
Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009).
Ali, O. A., Emerich, D., Dranoff, G. & Mooney, D. J. In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci. Transl. Med. 1, 8RA19 (2009).
Bencherif, S. A. et al. Injectable cryogel-based whole-cell cancer vaccines. Nat. Commun. 6, 7556 (2015).
Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015).
Randolph, G. J., Ochando, J. & Partida-Sánchez, S. Migration of dendritic cell subsets and their precursors. Annu. Rev. Immunol. 26, 293–316 (2008).
Dieu, M.-C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998).
Zuber, J. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 23, 877–889 (2009).
Palucka, K. & Banchereau, J. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 12, 265–277 (2012).
Delluc, S. et al. Dramatic efficacy improvement of a DC-based vaccine against AML by CD25 T cell depletion allowing the induction of a long-lasting T cell response. Cancer Immunol. Immunother. 58, 1669–1677 (2009).
Gattinoni, L., Powell, D. J., Rosenberg, S. A. & Restifo, N. P. Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol. 6, 383–393 (2006).
Davila, M. L. et al. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int. J. Hematol. 99, 361–371 (2014).
Gubin, M. M., Artyomov, M. N., Mardis, E. R. & Schreiber, R. D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J. Clin. Investig. 125, 3413–3421 (2015).
Ritchie, D. S. et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol. Ther. 21, 2122–2129 (2013).
Rosenblatt, J. et al. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci. Transl. Med. 8, 368RA171 (2016).
Fucikova, J. et al. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients. Blood 128, 3113–3124 (2016).
Pospori, C. et al. Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination. Blood 117, 6813–6824 (2011).
Kolb, H.-J. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112, 4371–4383 (2008).
Ho, V. et al. GM-CSF secreting leukemia cell vaccinations after allogeneic reduced-intensity peripheral blood stem cell transplantation (SCT) for advanced myelodysplastic syndrome (MDS) or refractory acute myeloid leukemia (AML). Blood 108, 3680–3680 (2006).
Ho, V. et al. GM-CSF secreting leukemia cell vaccination after allogeneic reduced intensity hematopoietic stem cell transplantation for advanced myeloid malignancies. Blood 112, 825–825 (2008).
Shah, N. J. et al. An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nat. Biotechnol. 37, 293–302 (2019).
SEER Cancer Statistics Review (National Cancer Institute, 2016).
Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013).
Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).
Rezvani, K. et al. Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies. Haematologica 96, 432–440 (2011).
Herbert, W. The mode of action of mineral-oil emulsion adjuvants on antibody production in mice. Immunology 14, 301–318 (1968).
Sykes, D. B. et al. Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia. Cell 167, 171–186 (2016).
Haladyna, J., Pasteur, T., Riedel, S., Perraud, A. & Bernt, K. Transient potential receptor melastatin-2 (TRPM2) does not influence murine MLL-AF9 driven AML leukemogenesis or in vitro response to chemotherapy. Exp. Hematol. 44, 596–602 (2016).
Wonderlich, J., Shearer, G., Livingstone, A. & Brooks, A. Induction and measurement of cytotoxic T lymphocyte activity. Curr. Protoc. Immunol. 72, 3.11.1–3.11.23 (2006).
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.
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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