Low-dose X-ray radiotherapy–radiodynamic therapy via nanoscale metal–organic frameworks enhances checkpoint blockade immunotherapy

Abstract

Checkpoint blockade immunotherapy relies on energized cytotoxic T cells attacking tumour tissue systemically. However, for many cancers, the reliance on T cell infiltration leads to low response rates. Conversely, radiotherapy has served as a powerful therapy for local tumours over the past 100 years, yet is rarely sufficient to cause systemic tumour rejection. Here, we describe a treatment strategy that combines nanoscale metal–organic framework (nMOF)-enabled radiotherapy–radiodynamic therapy with checkpoint blockade immunotherapy for both local and systemic tumour elimination. In mouse models of breast and colorectal cancer, intratumorally injected nMOFs treated with low doses of X-ray irradiation led to the eradication of local tumours and, when loaded with an inhibitor of the immune checkpoint molecule indoleamine 2,3-dioxygenase, the irradiated nMOFs led to consistent abscopal responses that rejected distal tumours. By combining the advantages of local radiotherapy and systemic tumour rejection via synergistic X-ray-induced in situ vaccination and indoleamine 2,3-dioxygenase inhibition, nMOFs may overcome some of the limitations of checkpoint blockade in cancer treatment.

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Fig. 1: Preparation and characterization of nMOFs.
Fig. 2: RDT and radiotherapy are two major mechanisms involved in X-ray-induced anticancer efficacy.
Fig. 3: In vivo anticancer efficacy of DBP-Hf and TBP-Hf.
Fig. 4: Abscopal effect of IDOi@DBP-Hf.
Fig. 5: Antitumour immunity of IDOi@DBP-Hf and low-dose X-ray.
Fig. 6: nMOFs enable synergistic RT–RDT and immunotherapy using extremely low doses of X-rays.

References

  1. 1.

    Couzin-Frankel, J. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Bentzen, S. M. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat. Rev. Cancer 6, 702–713 (2006).

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Timmerman, R. et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303, 1070–1076 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Whelan, T. J. et al. Long-term results of hypofractionated radiation therapy for breast cancer. N. Engl. J. Med. 362, 513–520 (2010).

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Barnett, G. C. et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat. Rev. Cancer 9, 134–142 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Formenti, S. C. & Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Barker, H. E., Paget, J. T., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Shahabi, V., Postow, M. A., Tuck, D. & Wolchok, J. D. Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy. Am. J. Clin. Oncol. 38, 90–97 (2015).

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. & Wolchok, J. D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185–202 (2014).

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl. Cancer Inst. 105, 256–265 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Dougherty, T. J. et al. Photodynamic therapy. J. Natl. Cancer Inst. 90, 889–905 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Castano, A. P., Mroz, P. & Hamblin, M. R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 6, 535–545 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Garg, A. D., Nowis, D., Golab, J. & Agostinis, P. Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity. Apoptosis 15, 1050–1071 (2010).

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Stolik, S., Delgado, J., Perez, A. & Anasagasti, L. Measurement of the penetration depths of red and near infrared light in human “ex vivo” tissues. J. Photochem. Photobiol. B Biol. 57, 90–93 (2000).

    Article  CAS  Google Scholar 

  19. 19.

    Hashiguchi, S. et al. Acridine orange excited by low-dose radiation has a strong cytocidal effect on mouse osteosarcoma. Oncology 62, 85–93 (2002).

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Wang, C. et al. Synergistic assembly of heavy metal clusters and luminescent organic bridging ligands in metal–organic frameworks for highly efficient X-ray scintillation. J. Am. Chem. Soc. 136, 6171–6174 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Katz, J. B., Muller, A. J. & Prendergast, G. C. Indoleamine 2,3‐dioxygenase in T‐cell tolerance and tumoral immune escape. Immunol. Rev. 222, 206–221 (2008).

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Okamoto, A. et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res. 11, 6030–6039 (2005).

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Brandacher, G. et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12, 1144–1151 (2006).

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Liu, X. et al. Selective inhibition of IDO1 effectively regulates mediators of antitumour immunity. Blood 115, 3520–3530 (2010).

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Platten, M., von Knebel Doeberitz, N., Oezen, I., Wick, W. & Ochs, K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front. Immunol. 5, 673 (2014).

    PubMed  Google Scholar 

  29. 29.

    Mautino, M. R. et al. Synergistic antitumor effects of combinatorial immune checkpoint inhibition with anti-PD-1/PD-L antibodies and the IDO pathway inhibitors NLG-919 and indoximod in the context of active immunotherapy. Cancer Res. 74, 5023 (2014).

    Article  Google Scholar 

  30. 30.

    Li, M. et al. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J. Immunother. Cancer 2, 21 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Zhuang, J. et al. Optimized metal–organic-framework nanospheres for drug delivery: evaluation of small-molecule encapsulation. ACS Nano 8, 2812–2819 (2014).

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    McKinlay, A. C. et al. Exceptional behavior over the whole adsorption−storage−delivery cycle for NO in porous metal organic frameworks. J. Am. Chem. Soc. 130, 10440–10444 (2008).

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Furukawa, H., Cordova, K. E., O’Keeffe, M. & Yaghi, O. M. The chemistry and applications of metal−organic frameworks. Science 341, 1230444 (2013).

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    He, C., Liu, D. & Lin, W. Nanomedicine applications of hybrid nanomaterials built from metal–ligand coordination bonds: nanoscale metal–organic frameworks and nanoscale coordination polymers. Chem. Rev. 115, 11079–11108 (2015).

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Levine, D. J. et al. Olsalazine-based metal–organic frameworks as biocompatible platforms for H2 adsorption and drug delivery. J. Am. Chem. Soc. 138, 10143–10150 (2016).

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Morris, W., Briley, W. E., Auyeung, E., Cabezas, M. D. & Mirkin, C. A. Nucleic acid–metal organic framework (MOF) nanoparticle conjugates. J. Am. Chem. Soc. 136, 7261–7264 (2014).

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Allen, T. M. & Cullis, P. R. Drug delivery systems: entering the mainstream. Science 303, 1818–1822 (2004).

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  39. 39.

    Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1, 0029 (2017).

    Article  Google Scholar 

  40. 40.

    Lovell, J. F. et al. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 10, 324–332 (2011).

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Ng, K. K. & Zheng, G. Molecular interactions in organic nanoparticles for phototheranostic applications. Chem. Rev. 115, 11012–11042 (2015).

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Carter, K. A. et al. Porphyrin–phospholipid liposomes permeabilized by near-infrared light. Nat. Commun. 5, 3546 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Wang, A. Z., Langer, R. & Farokhzad, O. C. Nanoparticle delivery of cancer drugs. Annu. Rev. Med. 63, 185–198 (2012).

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Lu, K., He, C. & Lin, W. Nanoscale metal–organic framework for highly effective photodynamic therapy of resistant head and neck cancer. J. Am. Chem. Soc. 136, 16712–16715 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. 45.

    Dai, R. et al. Electron crystallography reveals atomic structures of metal–organic nanoplates with M123-O)83-OH)82-OH)6 (M = Zr, Hf) secondary building units. Inorg. Chem. 56, 8128–8134 (2017).

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Cliffe, M. J. et al. Metal–organic nanosheets formed via defect-mediated transformation of a hafnium metal–organic framework. J. Am. Chem. Soc. 139, 5397–5404 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Tourneau, C. L. et al. A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 35, 6080 (2017).

    Article  Google Scholar 

  48. 48.

    Lu, K. et al. Chlorin-based nanoscale metal–organic framework systemically rejects colorectal cancers via synergistic photodynamic therapy and checkpoint blockade immunotherapy. J. Am. Chem. Soc. 138, 12502–12510 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Morris, W. et al. Synthesis, structure, and metalation of two new highly porous zirconium metal–organic frameworks. Inorg. Chem. 51, 6443–6445 (2012).

    Article  PubMed  CAS  Google Scholar 

  50. 50.

    Sheridan, C. Proof of concept for next-generation nanoparticle drugs in humans. Nat. Biotechnol. 30, 471–473 (2012).

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Seiwert, T. Y., Salama, J. K. & Vokes, E. E. The concurrent chemoradiation paradigm—general principles. Nat. Clin. Pract. Oncol. 4, 86–100 (2007).

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Fowler, J. Fractionated radiation therapy after Strandqvist. Acta Radiol. Oncol. 23, 209–216 (1984).

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    He, J. et al. The induction of partial resistance to photodynamic therapy by the protooncogene BCL‐2. Photochem. Photobiol. 64, 845–852 (1996).

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Yue, E. W. et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J. Med. Chem. 52, 7364–7367 (2009).

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Beatty, G. L. et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23, 3269–3276 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 56.

    Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Tsou, P., Katayama, H., Ostrin, E. J. & Hanash, S. M. The emerging role of B cells in tumor immunity. Cancer Res. 76, 5597–5601 (2016).

    Article  PubMed  CAS  Google Scholar 

  58. 58.

    Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).

    Article  PubMed  CAS  Google Scholar 

  59. 59.

    Weinstein, J. R. et al. IgM-dependent phagocytosis in microglia is mediated by complement receptor 3, not Fc⍺/μ receptor. J. Immunol. 195, 5309–5317 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    Wang, H., Coligan, J. E. & Morse, H. C. 3rd Emerging functions of natural IgM and its Fc receptor FCMR in immune homeostasis. Front. Immunol. 7, 99 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Chen, H. et al. Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment. Nano Lett. 15, 2249–2256 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 62.

    Siva, S., MacManus, M. P., Martin, R. F. & Martin, O. A. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett. 356, 82–90 (2015).

    Article  PubMed  CAS  Google Scholar 

  63. 63.

    Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat. Rev. 41, 503–510 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Wei, W. Z. et al. Concurrent induction of antitumour immunity and autoimmune thyroiditis in CD4+CD25+ regulatory T cell-depleted mice. Cancer Res. 65, 8471–8478 (2005).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank C. Poon and Z. Lin for experimental help. We also thank S. J. Kron and M. S. Lesniak for kindly providing the cell lines. We acknowledge the National Cancer Institute (U01–CA198989 and R21-CA195075A), University of Chicago Medicine Comprehensive Cancer Center (NIH CCSG: P30 CA014599), Chemistry–Biology Interface training grant (NIH 5T32GM008720-15) and Ludwig Center for Metastasis Research for funding support.

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W.L., C.H., K.L. and N.G. conceived the project. C.H., K.L., N.G., C.C., K.N., G.L., H.T. and C.P. performed the experiments and analysed the results. C.H., K.L., C.C., Y.-X.F., M.T.S., R.R.W. and W.L. wrote the manuscript.

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Correspondence to Wenbin Lin.

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Competing interests

W.L. is the founder of RiMO Therapeutics, which licensed the RT–RDT technology from The University of Chicago. R.R.W. is an advisor to RiMO Therapeutics.

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Lu, K., He, C., Guo, N. et al. Low-dose X-ray radiotherapy–radiodynamic therapy via nanoscale metal–organic frameworks enhances checkpoint blockade immunotherapy. Nat Biomed Eng 2, 600–610 (2018). https://doi.org/10.1038/s41551-018-0203-4

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