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Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy

Nature Nanotechnology volume 12, pages 763–769 (2017)Cite this article

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Abstract

Tumour-targeted immunotherapy offers the unique advantage of specific tumouricidal effects with reduced immune-associated toxicity1,2. However, existing platforms suffer from low potency, inability to generate long-term immune memory and decreased activities against tumour-cell subpopulations with low targeting receptor levels3,4,5. Here we adopted a modular design approach that uses colloidal nanoparticles as substrates to create a multivalent bi-specific nanobioconjugate engager (mBiNE) to promote selective, immune-mediated eradication of cancer cells. By simultaneously targeting the human epidermal growth factor receptor 2 (HER2) expressed by cancer cells6 and pro-phagocytosis signalling mediated by calreticulin7, the mBiNE stimulated HER2-targeted phagocytosis and produced durable antitumour immune responses against HER2-expressing tumours. Interestingly, although the initial immune activation mediated by the mBiNE was receptor dependent, the subsequent antitumour immunity also generated protective effects against tumour-cell populations that lacked the HER2 receptor. Thus, the mBiNE represents a new targeted, nanomaterial-immunotherapy platform to stimulate innate and adaptive immunity and promote a universal antitumour response.

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Figure 1: The mBiNE enables bi-specific engagement of cancerous and professional APCs in a targeted manner.
Figure 2: The mBiNE promotes receptor-targeted phagocytosis of cancer cells by macrophages and enhances downstream immune activation mediated by professional APCs.
Figure 3: The mBiNE elicits antitumour immune responses in vivo in a receptor-targeted manner.
Figure 4: The mBiNE induces systemic, durable antitumour immunity.

References

  1. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  Google Scholar 

  2. Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).

    Article  CAS  Google Scholar 

  3. Baeuerle, P. A. & Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 69, 4941–4944 (2009).

    Article  CAS  Google Scholar 

  4. Kalos, M. & June, C. H. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49–60 (2013).

    Article  CAS  Google Scholar 

  5. Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013).

    Article  CAS  Google Scholar 

  6. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  CAS  Google Scholar 

  7. Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).

    Article  CAS  Google Scholar 

  8. Blattman, J. D. & Greenberg, P. D. Cancer immunotherapy: a treatment for the masses. Science 305, 200–205 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  Google Scholar 

  11. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  Google Scholar 

  12. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  Google Scholar 

  13. Nghiem, P. T. et al. PD-1 blockade with pembrolizumab in advanced Merkel cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).

    Article  CAS  Google Scholar 

  14. Topalian, S. L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  Google Scholar 

  15. Li, A. V. et al. Generation of effector memory T cell–based mucosal and systemic immunity with pulmonary nanoparticle vaccination. Sci. Transl. Med. 5, 204ra130 (2013).

    Google Scholar 

  16. Cho, N. H. et al. A multifunctional core–shell nanoparticle for dendritic cell-based cancer immunotherapy. Nat. Nanotech. 6, 675–682 (2011).

    Article  CAS  Google Scholar 

  17. Lizotte, P. H. et al. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat. Nanotech. 11, 295–303 (2016).

    Article  CAS  Google Scholar 

  18. Li, H., Li, Y., Jiao, J. & Hu, H. M. Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nat. Nanotech. 6, 645–650 (2011).

    Article  CAS  Google Scholar 

  19. Kalinski, P. et al. Dendritic cell-based therapeutic cancer vaccines: what we have and what we need. Future Oncol. 5, 379–390 (2009).

    Article  CAS  Google Scholar 

  20. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2006).

    Article  Google Scholar 

  21. Jiang, W., Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotech. 3, 145–150 (2008).

    Article  CAS  Google Scholar 

  22. Park, S. G. et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).

    Article  CAS  Google Scholar 

  23. Ma, Y. et al. Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development. J. Immunol. 90, 5588–5599 (2013).

    Article  Google Scholar 

  24. Feng, M. et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc. Natl Acad. Sci. USA 112, 2145–2150 (2014).

    Article  Google Scholar 

  25. Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).

    Article  CAS  Google Scholar 

  26. Klebanoff, C. A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102, 9571–9576 (2005).

    Article  CAS  Google Scholar 

  27. Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–324 (2005).

    Article  CAS  Google Scholar 

  28. Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009).

    Article  CAS  Google Scholar 

  29. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    Article  CAS  Google Scholar 

  30. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy Science 348, 56–61 (2015).

    Article  CAS  Google Scholar 

  31. Qie, Y. et al. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. Sci. Rep. 6, 26269 (2016).

    Article  CAS  Google Scholar 

  32. Jiang, W., Mardyani, S., Fischer, H. & Chan, W. C. W. Design and characterization of lysine cross-linked mercapto-acid biocompatible quantum dots. Chem. Mater. 18, 872–878 (2006).

    Article  CAS  Google Scholar 

  33. Mosser, D. M. & Zhang, X. Activation of murine macrophages. Curr. Protocol. Immunol. 83, 14.2.1–14.2.8 (2008).

    Google Scholar 

  34. Weiskopf, K. et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341, 88–91 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank P. Anastasiadis, L. Petrucelli, H. Crawford, J. Copland, D. Radisky, T. Gonwa and D. Page and his veterinary team for reagents and helpful discussions. We also thank L. Lewis-Tuffin for her help with flow cytometer and confocal experiments, J. A. Knight, R. Feathers, H.-J. Wen and E. E. Miller for their helpful discussions, and B. Edenfield for her assistance with immunohistological experiments. Finally, we thank C. Wogan from MD Anderson's Division of Radiation Oncology for editorial contributions and AXS Studio for preparing Fig. 4d. Research reported here was supported by the James C. and Sara K. Kennedy Award from Mayo Clinic (B.Y.S.K), Jorge and Leslie Bacardi Fund for the study of Regenerative Medicine, Mayo Clinic Center for Regenerative Medicine (B.Y.S.K.), Mayo Clinic Center for Individualized Medicine Gerstner Family Award (B.Y.S.K.), Helene Houle Mayo Clinic Career Development Award in Neurologic Surgery (B.Y.S.K.), Mayo Clinic Neuroregenerative Medicine Initiative for Neuro-Oncology Research (B.Y.S.K.), China Scholarships Council (No. 201406100114, H.Y.), DeMars Family Mayo Clinic Development Fund (B.Y.S.K.) and Strawn Family Mayo Clinic Development Fund (B.Y.S.K.).

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Author notes

  1. Hengfeng Yuan, Wen Jiang, Christina A. von Roemeling and Yaqing Qie: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, Zhongshan Hospital, Fudan University, 111 Yixueyuan Road, Xuhui, Shanghai, China

    Hengfeng Yuan

  2. Department of Neurosurgery, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Hengfeng Yuan, Christina A. von Roemeling, Yaqing Qie, Xiujie Liu, Yuanxin Chen, Robert E. Wharen & Betty Y. S. Kim

  3. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Wen Jiang

  4. Mayo Graduate School, Mayo Clinic College of Medicine, 200 1st Street, Rochester, 55902, Minnesota, USA

    Christina A. von Roemeling

  5. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Yifan Wang

  6. Department of Neurosurgery, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, 77030, Texas, USA

    Kyuson Yun

  7. Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Guojun Bu & Betty Y. S. Kim

  8. Department of Cancer Biology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Keith L. Knutson & Betty Y. S. Kim

  9. Department of Immunology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    Keith L. Knutson

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  1. Hengfeng Yuan
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Contributions

H.Y., W.J. and B.Y.S.K. conceived the study and designed the experiments. H.Y., C.A.V.R., Y.Q., X.L. and Y.C. performed the experiments and generated the data. H.Y., C.A.V. R., W.J., Y.W., R.E.W., K.Y., G.B., K.L.K. and B.Y.S.K. analysed the data and interpreted the results. All authors helped to write the paper.

Corresponding authors

Correspondence to Wen Jiang or Betty Y. S. Kim.

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The Mayo Clinic has filed a patent application on the technology and intellectual property reported here.

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Yuan, H., Jiang, W., von Roemeling, C. et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nature Nanotech 12, 763–769 (2017). https://doi.org/10.1038/nnano.2017.69

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