Abstract

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.

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Acknowledgements

We thank K.D. Wittrup (MIT) for the gift of the engineered IL-2-Fc constructs and the Koch Institute Swanson Biotechnology Center for technical support on flow cytometry, IVIS imaging and MALDI mass spectrometry. This work was supported in part by the Ragon Institute of MGH, MIT and Harvard (D.J.I.), the Melanoma Research Alliance (award 306833; D.J.I.), the NIH (Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute and CA172164; D.J.I.) and the Koch Institute Marble Center for Cancer Nanomedicine (D.J.I.). L.T. was funded by a Cancer Research Institute (CRI) Irvington Postdoctoral Fellowship, and Y.Z. was supported by a National Science fellowship from the Agency for Science, Technology and Research, Singapore. L.T. and Y.-Q.X. were supported by the ISREC Foundation with a donation from the Biltema Foundation and Swiss National Science Foundation (project grant 315230_173243). M.V.M. was supported by NIH grant CA K08166039. D.J.I. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Li Tang

    Present addresses: Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Institute of Materials Science and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

    • Li Tang
    •  & Yiran Zheng

    These authors contributed equally to this work.

Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.

    • Li Tang
    • , Yiran Zheng
    • , Mariane Bandeira Melo
    • , Llian Mabardi
    • , Na Li
    •  & Darrell J Irvine
  2. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Li Tang
    •  & Darrell J Irvine
  3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Li Tang
    • , Yiran Zheng
    • , Mariane Bandeira Melo
    • , Na Li
    •  & Darrell J Irvine
  4. Cellular Immunotherapy Program, Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.

    • Ana P Castaño
    •  & Marcela V Maus
  5. Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

    • Yu-Qing Xie
  6. Vaccine Center, Wistar Institute, Philadelphia, Pennsylvania, USA.

    • Sagar B Kudchodkar
  7. Altor BioScience Corporation, Miramar, Florida, USA.

    • Hing C Wong
    •  & Emily K Jeng
  8. Harvard Medical School, Boston, Massachusetts, USA.

    • Marcela V Maus
  9. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Darrell J Irvine
  10. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Darrell J Irvine

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Contributions

L.T., Y.Z., M.B.M. and D.J.I. designed the in vitro and syngeneic mouse experiments; H.C.W. and E.K.J. provided ALT-803; L.T., Y.Z., D.J.I., A.P.C., S.B.K. and M.V.M. designed the studies with the humanized mice; L.T., Y.Z., L.M., M.B.M., Y.-Q.X., N.L., A.P.C. and S.B.K. performed the experiments; L.T., Y.Z., M.B.M. and D.J.I. analyzed the data and wrote the manuscript; and all authors edited the manuscript.

Competing interests

D.J.I., L.T., and Y.Z. are inventors on licensed patents related to the technology described in this manuscript. D.J.I. is a co-founder of Torque Therapeutics, which licensed patents related to this technology.

Corresponding authors

Correspondence to Li Tang or Darrell J Irvine.

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DOI

https://doi.org/10.1038/nbt.4181