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Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

Nature Materials volume 11, pages 895–905 (2012)Cite this article

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Abstract

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

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Figure 1: Fabrication of the nLG particle system.
Figure 2: Controlled release clearance and biodistribution in healthy animals.
Figure 3: Clinical effects of nLG therapy on subcutaneous and metastatic melanoma.
Figure 4: Biodistribution to subcutaneous tumours after systemic administration.
Figure 5: The adaptive immune response and mechanism of nLG–SB + IL-2 action.
Figure 6: Role of NK cells in tumour immunotherapy after combination delivery.

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Acknowledgements

The authors would like to thank R. Murelli and D. Spiegel for assistance with polymer synthesis; P. McEnaney, S. Royce-Hynes, J. Bertram and Q. Wang for helpful discussions and assistance with the procedures. The work was supported in part by NIH through grants R01-HL085416 and R01-EB008260 (T.M.F.); an NIH Autoimmunity Center of Excellence Pilot Award (U19AI082713; T.M.F); a Public Health Grant (HL-55397; T.M.F.); an NSF CAREER grant (T.M.F.); a Yale Skin SPORE Career Development Award (S.H.W.); the Howard Hughes Medical Institute (R.A.F.); the Yale Cancer Center (S.H.W.), and a post-doctoral fellowship from the Pew Charitable Trust: Pew Latin American Fellow Program in Biomedical Sciences (P.L.L.) and the Yale Rheumatologic Disease Research Core Center P30AR053495.

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Author notes

  1. Jason Park, Stephen H. Wrzesinski and Eric Stern: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biomedical and Environmental Engineering, Yale University School of Engineering and Applied Sciences, New Haven, Connecticut 06511, USA

    Jason Park, Eric Stern, Michael Look, Jason Criscione, Ragy Ragheb, Steven M. Jay, Stacey L. Demento, Atu Agawu & Tarek M. Fahmy

  2. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06511, USA

    Stephen H. Wrzesinski, Paula Licona Limon, Anthony F. Ferrandino & Richard A. Flavell

  3. Yale Cancer Center, New Haven, Connecticut 06511, USA

    Stephen H. Wrzesinski, Richard A. Flavell & Tarek M. Fahmy

  4. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA

    David Gonzalez & Ann Habermann

  5. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06511, USA

    Richard A. Flavell

  6. Department of Chemical and Environmental Engineering, Yale University School of Engineering and Applied Sciences, New Haven, Connecticut 06511, USA

    Tarek M. Fahmy

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Contributions

J.P., E.S., S.H.W., R.A.F. and T.M.F. designed all of the experiments for this study. R.R helped synthesize the polymer with J.C., J.P. and E.S. T.M.F. conceived the formulation and E.S., J.P., S.M.J., A.A. and T.M.F. developed and characterized the particles. J.P., E.S., S.H.W., P.L.L. and S.L.D. performed in vivo experiments. J.P., S.H.W. and P.L.L. performed FACS analyses and in vitro characterization experiments. M.L. performed toxicology experiments, nLG characterization experiments and part of the statistical analysis. R.A.F. and T.M.F. initiated the research and supervised the program. A.H. and D.S. helped perform and analyse the intravital imaging microscopy work together with J.P. J.P., E.S., S.H.W. and T.M.F. wrote the manuscript. T.M.F. edited the manuscript.

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Correspondence to Tarek M. Fahmy.

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Park, J., Wrzesinski, S., Stern, E. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nature Mater 11, 895–905 (2012). https://doi.org/10.1038/nmat3355

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