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Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses

Abstract

Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against hypoxic solid tumours and distant metastases. Here, we show that intratumoral injection, in mouse and rabbit xenografts and in patient-derived mouse xenografts, of a sodium alginate formulation containing catalase (Cat) labelled with the therapeutic 131I radioisotope enables long-term relief of tumour hypoxia and complete tumour elimination at low radioactivity doses. On injection, the soluble polysaccharide rapidly transforms into a hydrogel in the presence of endogenous Ca2+, fixing 131I-Cat within the tumours. We also show that local radiotherapy with a formulation that includes the immunostimulatory CpG oligonucleotide combined with systemic checkpoint-blockade therapy using an anti-CTLA-4 antibody leads to metastasis inhibition and protection against tumour rechallenge. The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments that can be combined with systemic therapeutic responses, for the inhibition of tumour metastasis and the prevention of tumour recurrence in patients with advanced-stage cancer.

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Fig. 1: Gelation behaviour of the hybrid system.
Fig. 2: In vivo gelation inside the tumour.
Fig. 3: RIT treatment of local tumours by 131I-Cat/ALG.
Fig. 4: Tumour metastasis inhibition with RIT immunotherapy.
Fig. 5: Immune memory effect.

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Acknowledgements

This work was partially supported by the National Basic Research Programs of China (973 Program) (2016YFA0201200), the National Natural Science Foundation of China (51525203, 51761145041, 81471716 and 31400861), the Collaborative Innovation Center of Suzhou Nano Science and Technology, a ‘111’ program from the Ministry of Education of China, and a Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Y.C., K.Y. and Z.L. designed the project. Y.C., L.X., C.L., L.F., J.X., Z.D., L.T. and X.Y. performed the experiments. Y.C., K.Y. and Z.L. analysed and interpreted the data. Z.L. supervised the overall research. Y.C. and Z.L. wrote the manuscript.

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Correspondence to Kai Yang or Zhuang Liu.

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Chao, Y., Xu, L., Liang, C. et al. Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses. Nat Biomed Eng 2, 611–621 (2018). https://doi.org/10.1038/s41551-018-0262-6

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