Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Biopolymer implants enhance the efficacy of adoptive T-cell therapy

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Krebs, S., Rodriguez-Cruz, T.G., Derenzo, C. & Gottschalk, S. Genetically modified T cells to target glioblastoma. Front. Oncol. 3, 322 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kandalaft, L.E., Powell, D.J. Jr. & Coukos, G. A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J. Transl. Med. 10, 157 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rosenberg, S.A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Robbins, P.F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hinrichs, C.S.a. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. J. Clin. Oncol. 32, 5s (suppl; abstr LBA3008) (2014).

    Article  Google Scholar 

  7. Kershaw, M.H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yaghoubi, S.S. et al. Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat. Clin. Pract. Oncol. 6, 53–58 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Lamers, C.H. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Baldwin, A.D. & Kiick, K.L. Polysaccharide-modified synthetic polymeric biomaterials. Biopolymers 94, 128–140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wojtowicz, A.M. et al. Coating of biomaterial scaffolds with the collagen-mimetic peptide GFOGER for bone defect repair. Biomaterials 31, 2574–2582 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Miller, M.J., Wei, S.H., Cahalan, M.D. & Parker, I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl. Acad. Sci. USA 100, 2604–2609 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mamaeva, V., Sahlgren, C. & Linden, M. Mesoporous silica nanoparticles in medicine–recent advances. Adv. Drug Deliv. Rev. 65, 689–702 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Rubinstein, M.P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc. Natl. Acad. Sci. USA 103, 9166–9171 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maus, M.V. et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4–1BB. Nat. Biotechnol. 20, 143–148 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Janát-Amsbury, M.M., Yockman, J.W., Anderson, M.L., Kieback, D.G. & Kim, S.W. Comparison of ID8 MOSE and VEGF-modified ID8 cell lines in an immunocompetent animal model for human ovarian cancer. Anticancer Res. 26, 2785–2789 (2006).

    PubMed  Google Scholar 

  17. Conejo-Garcia, J.R. et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat. Med. 10, 950–958 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Charles, K.A. et al. The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J. Clin. Invest. 119, 3011–3023 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Scarlett, U.K. et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J. Exp. Med. 209, 495–506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sentman, C.L. & Meehan, K.R. NKG2D CARs as cell therapy for cancer. Cancer J. 20, 156–159 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ali, O.A., Emerich, D., Dranoff, G. & Mooney, D.J. In situ regulation of DC subsets and T cells mediates tumor regression in mice. Sci. Transl. Med. 1, 8ra19 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kauer, T.M., Figueiredo, J.L., Hingtgen, S. & Shah, K. Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. Nat. Neurosci. 15, 197–204 (2012).

    Article  CAS  Google Scholar 

  23. Hori, Y., Winans, A.M., Huang, C.C., Horrigan, E.M. & Irvine, D.J. Injectable dendritic cell-carrying alginate gels for immunization and immunotherapy. Biomaterials 29, 3671–3682 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Pule, M.A. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264–1270 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Peres, E. et al. High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors. Neuropediatrics 39, 151–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Tumeh, P.C. et al. The impact of ex vivo clinical grade activation protocols on human T-cell phenotype and function for the generation of genetically modified cells for adoptive cell transfer therapy. J. Immunother. 33, 759–768 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rosenberg, S.A. Cell transfer immunotherapy for metastatic solid cancer–what clinicians need to know. Nat. Rev. Clin. Oncol. 8, 577–585 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stone, J.D., Chervin, A.S., Schreiber, H. & Kranz, D.M. Design and characterization of a protein superagonist of IL-15 fused with IL-15Ralpha and a high-affinity T cell receptor. Biotechnol. Prog. 28, 1588–1597 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Boontheekul, T., Kong, H.J. & Mooney, D.J. Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials 26, 2455–2465 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Erskine, C.L., Henle, A.M. & Knutson, K.L. Determining optimal cytotoxic activity of human Her2neu specific CD8 T cells by comparing the Cr51 release assay to the xCELLigence system. J. Vis. Exp. 2012, e3683 (2012).

    Google Scholar 

Download references

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandria M Taber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ilona Jileaeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ericka P Pegues
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles L Sentman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias T Stephan
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.3104

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research