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Biopolymer implants enhance the efficacy of adoptive T-cell therapy

Nature Biotechnology volume 33, pages 97–101 (2015)Cite this article

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Abstract

Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.

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Figure 1: Biomaterial carriers can deliver anticancer T cells to prevent recurrence or eliminate inoperable tumors.
Figure 2: Porous polysaccharide scaffolds functionalized with appropriate adhesion molecules and stimulatory cues support rapid migration, robust expansion and sustained release of T cells.
Figure 3: Material-deployed T cells robustly expand in tumor tissue, where they reduce residual disease and relapse.

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Acknowledgements

We thank D. Ehlert (cognitionstudio.com) for the design of the illustration in Figure 1. This work was supported in part by the Fred Hutchinson Cancer Research Center's Immunotherapy Initiative with funds provided by the Bezos Family Foundation, the National Cancer Institute (NCI; RO1 CA181413), the George and Margaret McLane Foundation, the Breast Cancer Development Research Program funded by the Safeway Foundation and the Seattle Cancer Consortium Breast SPORE (NCI P50 CA138293, PI: Peggy Porter) and the Pacific Ovarian Cancer Research Consortium (NCI P50 CA83636, PI: Nicole Urban). We thank K. Roby (University of Kansas Medical Center, Kansas City, KS, USA) for giving us the murine ovarian cancer cell line ID8. SFG-CBR-luc (expressing click beetle red luciferase), SFG-F-luc (expressing firefly luciferase), and SFG-B7.1 and SFG-4-1BBL (encoding the costimulatory ligands B7.1 and 4-1BBL) vectors were kindly provided by M. Sadelain (Memorial Sloan-Kettering Cancer Center, New York).

Author information

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Sirkka B Stephan, Alexandria M Taber & Matthias T Stephan

  2. Technology Access Foundation (TAF) Academy, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Ilona Jileaeva, Ericka P Pegues & Matthias T Stephan

  3. Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA

    Charles L Sentman

  4. Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, Washington, USA

    Matthias T Stephan

  5. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington, USA

    Matthias T Stephan

Authors
  1. Sirkka B Stephan
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Contributions

S.B.S. designed and performed experiments, and analyzed and interpreted data. A.M.T. helped perform experiments, I.J. and E.P.P. helped prepare scaffolds and microparticles, C.L.S. provided NKG2D CARs constructs, and M.T.S. designed the study, performed experiments, analyzed and interpreted data, and wrote the manuscript.

Corresponding author

Correspondence to Matthias T Stephan.

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Competing interests

The NKG2D CAR technology used in this paper is licensed by Celdara Medical, LLC. Dr. Sentman and Celdara are developing the technology for clinical use, for which he receives compensation. These activities are in full compliance with the policies of Dartmouth College.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1-20 (PDF 12824 kb)

Porous polysaccharide scaffolds coated with collagen-mimetic peptide support rapid lymphocyte motility.

This time lapse videomicroscopy series compares T cell migration through unmodified or GFOGER-peptide functionalized alginate scaffolds (see also Fig. 2a). A 10-fold magnified image is shown in the inset to illustrate pore-to-pore migration of T cells. Trajectories of individual cells tracked for 30 min are shown in the lower panels. Every color represents an individual cell. Scale bar: 25 μm. (MOV 11467 kb)

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Stephan, S., Taber, A., Jileaeva, I. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat Biotechnol 33, 97–101 (2015). https://doi.org/10.1038/nbt.3104

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