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In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy

Nature Biomedical Engineering volume 1, Article number: 0011 (2017) Cite this article

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Abstract

Cancer recurrence after surgical resection remains a significant challenge in cancer therapy. Platelets, which accumulate in wound sites and interact with circulating tumour cells (CTCs), can however trigger inflammation and repair processes in the remaining tumour microenvironment. Inspired by this intrinsic ability of platelets and the clinical success of immune checkpoint inhibitors, here we show that conjugating anti-PDL1 (engineered monoclonal antibodies against programmed-death ligand 1) to the surface of platelets can reduce post-surgical tumour recurrence and metastasis. Using mice bearing partially removed primary melanomas (B16-F10) or triple-negative breast carcinomas (4T1), we found that anti-PDL1 was effectively released on platelet activation by platelet-derived microparticles, and that the administration of platelet-bound anti-PDL1 significantly prolonged overall mouse survival after surgery by reducing the risk of cancer regrowth and metastatic spread. Our findings suggest that engineered platelets can facilitate the delivery of the immunotherapeutic anti-PDL1 to the surgical bed and target CTCs in the bloodstream, thereby potentially improving the objective response rate.

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Figure 1: In situ activation of P–aPDL1 promoted release of anti-PDL1 (aPDL1) and cytokines.
Figure 2: P–aPDL1 reduced in vivo recurrence of melanoma tumours in the surgical bed.
Figure 3: P–aPDL1 triggered a robust, T-cell-mediated anti-tumour immune response.
Figure 4: P–aPDL1 reduced metastasis and local recurrence of melanoma.
Figure 5: P–aPDL1 treatment of recurrent triple negative 4T1 tumour.

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Acknowledgements

This work was supported by grants from the Alfred P. Sloan Foundation (Sloan Research Fellowship), NC TraCS, the National Institutes of Health (Clinical and Translational Science Award (CTSA, NIH grant 1L1TR001111) to Z.G.) and a pilot grant from the University of North Carolina (UNC) Cancer Center. We acknowledge L. Huang at UNC at Chapel Hill for providing the B16F10-Luc-GFP and 4T1-Luc-GFP cell lines.

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  1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, 27695, North Carolina, USA

    Chao Wang, Wujin Sun, Yanqi Ye, Quanyin Hu, Hunter N. Bomba & Zhen Gu

  2. Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Chao Wang, Wujin Sun, Yanqi Ye, Quanyin Hu & Zhen Gu

  3. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Zhen Gu

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Contributions

C.W. and Z.G. designed the project. C.W., W.S., Y.Y and Q.H. performed the experiments. All authors analysed and interpreted the data. All authors contributed to the writing of the manuscript. All authors discussed the results and implications and edited the manuscript at all stages.

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Correspondence to Zhen Gu.

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Z.G. and C.W. have a pending patent entitled ‘Platelets for delivery of cancer immunotherapeutics’ (patent number, 10620-039PV1).

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Wang, C., Sun, W., Ye, Y. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat Biomed Eng 1, 0011 (2017). https://doi.org/10.1038/s41551-016-0011

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