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

Nature Biomedical Engineering volume 2, pages 600–610 (2018)Cite this article

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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.

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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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  1. These authors contributed equally: Kuangda Lu, Chunbai He and Nining Guo.

Authors and Affiliations

  1. Department of Chemistry, The University of Chicago, Chicago, IL, USA

    Kuangda Lu, Chunbai He, Nining Guo, Christina Chan, Kaiyuan Ni, Guangxu Lan & Wenbin Lin

  2. The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

    Nining Guo & Ralph R. Weichselbaum

  3. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    Nining Guo, Charles Pelizzari, Michael T. Spiotto & Ralph R. Weichselbaum

  4. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Haidong Tang & Yang-Xin Fu

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Contributions

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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