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.

Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours

Nature Biomedical Engineering volume 4, pages 195–206 (2020)Cite this article

Subjects

Abstract

Micropatterned nickel titanium (commonly known as nitinol) thin films with complex designs, high structural resolution and excellent biocompatibility can be cheaply fabricated using magnetron sputtering. Here, we show that these benefits can be leveraged to fabricate micromesh implants that are loaded with tumour-specific human chimeric antigen receptor (CAR)-T cells for the treatment of solid tumours. In a mouse model of non-resectable ovarian cancer, the cell-loaded nitinol thin films spatially conformed to the implantation site, fostered the rapid expansion of T cells, delivered a high density of T cells directly to the tumour and significantly improved animal survival. We also show that self-expandable stents that were coated with T-cell-loaded films and implanted into subcutaneous tumours in mice improved the duration of stent patency by delaying tumour ingrowth. By providing direct access to tumours, CAR-T-cell-loaded micropatterned nitinol thin films can improve the effects of cell-based therapies.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Fig. 1: TFN micromeshes that are functionalized with appropriate adhesion molecules and stimulatory cues can support rapid migration and robust expansion of T cells.
Fig. 2: Rapid and predictable T-cell seeding can be defined by bioengineered TFN porosity patterns.
Fig. 3: Sustained release of T cells from bioactive TFN micromeshes.
Fig. 4: Culture on bioactive TFN films does not drive T-cell exhaustion.
Fig. 5: Launching ovarian-cancer-specific CAR-T cells from bioactive TFN micromeshes can eradicate established multifocal disease.
Fig. 6: Thin-film-deployed T cells robustly expand in tumour tissue.
Fig. 7: TFN membranes functionalized with CAR-T cells are biocompatible.
Fig. 8: Releasing cancer-specific T cells from TFN stents prevents tumour ingrowth and improves patency duration.

Data availability

The authors declare that all data supporting the findings of this study are provided within the paper and the Supplementary Information.

References

  1. Saigal, A. & Fonte, M. Solid, shape recovered “bulk” nitinol: part I—tension-compression asymmetry. Mat. Sci. Eng. A 528, 5536–5550 (2011).

    CAS  Google Scholar 

  2. Wang, X. B., Verlinden, B. & Van Humbeeck, J. Effect of post-deformation annealing on the R-phase transformation temperatures in NiTi shape memory alloys. Intermetallics 62, 43–49 (2015).

    CAS  Google Scholar 

  3. Chan, C. W., Chan, S. H. J., Man, H. C. & Ji, P. 1-D constitutive model for evolution of stress-induced R-phase and localized Luders-like stress-induced martensitic transformation of super-elastic NiTi wires. Int. J. Plasticity 32-33, 85–105 (2012).

    CAS  Google Scholar 

  4. Polatidis, E., Zotov, N., Bischoff, E. & Mittemeijer, E. J. The effect of cyclic tensile loading on the stress-induced transformation mechanism in superelastic NiTi alloys: an in-situ X-ray diffraction study. Scripta Mater. 100, 59–62 (2015).

    CAS  Google Scholar 

  5. Ho, K. K. & Carman, G. P. Sputter deposition of NiTi thin film shape memory alloy using a heated target. Thin Solid Films 370, 18–29 (2000).

    CAS  Google Scholar 

  6. Cha, J. O., Nam, T. H., Alghusun, M. & Ahn, J. S. Composition and crystalline properties of TiNi thin films prepared by pulsed laser deposition under vacuum and in ambient Ar gas. Nanoscale Res. Lett. 7, 37 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. Shayan, M., Jankowitz, B. T., Shridhar, P. & Chun, Y. Use of micropatterned thin film nitinol in carotid stents to augment embolic protection. J. Funct. Biomater. 7, 34 (2016).

    PubMed Central  Google Scholar 

  8. Chun, Y. et al. An in vivo pilot study of a microporous thin film nitinol-covered stent to assess the effect of porosity and pore geometry on device interaction with the vessel wall. J. Biomater. Appl. 31, 1196–1202 (2017).

    CAS  PubMed  Google Scholar 

  9. Shayan, M. & Chun, Y. An overview of thin film nitinol endovascular devices. Acta Biomater. 21, 20–34 (2015).

    CAS  PubMed  Google Scholar 

  10. Oliveira, J. M. et al. Hydrogel-based scaffolds to support intrathecal stem cell transplantation as a gateway to the spinal cord: clinical needs, biomaterials, and imaging technologies. NPJ Regen. Med. 3, 8 (2018).

    PubMed  PubMed Central  Google Scholar 

  11. Osama, I. et al. In vitro studies on space-conforming self-assembling silk hydrogels as a mesenchymal stem cell-support matrix suitable for minimally invasive brain application. Sci. Rep. 8, 13655 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Snyder, T. N., Madhavan, K., Intrator, M., Dregalla, R. C. & Park, D. A fibrin/hyaluronic acid hydrogel for the delivery of mesenchymal stem cells and potential for articular cartilage repair. J. Biol. Eng. 8, 10 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Machula, H., Ensley, B. & Kellar, R. Electrospun tropoelastin for delivery of therapeutic adipose-derived stem cells to full-thickness dermal wounds. Adv. Wound Care 3, 367–375 (2014).

    Google Scholar 

  14. Dotti, G., Gottschalk, S., Savoldo, B. & Brenner, M. K. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol. Rev. 257, 107–126 (2014).

    CAS  PubMed  Google Scholar 

  15. Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Turtle, C. J. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J. Clin. Oncol. 35, 3010–3020 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Mirzaei, H. R., Rodriguez, A., Shepphird, J., Brown, C. E. & Badie, B. Chimeric antigen receptors T cell therapy in solid tumor: challenges and clinical applications. Front. Immunol. 8, 1850 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Folch, E. & Keyes, C. Airway stents. Ann. Cardiothorac. Surg. 7, 273–283 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. Kim, E. J. & Kim, Y. J. Stents for colorectal obstruction: past, present, and future. World J. Gastroenterol. 22, 842–852 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pavlovic, K., Lange, D. & Chew, B. H. Stents for malignant ureteral obstruction. Asian J. Urol. 3, 142–149 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. Kamiyama, Y. et al. Stent failure in the management of malignant extrinsic ureteral obstruction: risk factors. Int. J. Urol. 18, 379–382 (2011).

    PubMed  Google Scholar 

  22. Asakawa, J. et al. Treatment outcomes of ureteral stenting for malignant extrinsic ureteral obstruction: a comparison between polymeric and metallic stents. Cancer Manag. Res. 10, 2977–2982 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. Ballard, D. D., Rahman, S., Ginnebaugh, B., Khan, A. & Dua, K. S. Safety and efficacy of self-expanding metal stents for biliary drainage in patients receiving neoadjuvant therapy for pancreatic cancer. Endosc. Int. Open 6, E714–E721 (2018).

    PubMed  PubMed Central  Google Scholar 

  24. Chun, Y. J., Levi, D. S., Mohanchandra, K. P., Fishbein, M. C. & Carman, G. P. Novel micro-patterning processes for thin film NiTi vascular devices. Smart Mater. Struct. 19, 105021 (2010).

    Google Scholar 

  25. Ding, Y. et al. Preclinical testing of a novel thin film nitinol flow-diversion stent in a rabbit elastase aneurysm model. AJNR Am. J. Neuroradiol. 37, 497–501 (2016).

    CAS  PubMed  Google Scholar 

  26. Spotnitz, W. D. Fibrin sealant: the only approved hemostat, sealant, and adhesive-a laboratory and clinical perspective. ISRN Surg. 2014, 203943 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. Zou, Z. et al. Cytotoxic T lymphocyte trafficking and survival in an augmented fibrin matrix carrier. PLoS ONE 7, e34652 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. Pounds, R. et al. Diaphragm disease in advanced ovarian cancer: predictability of pre-operative imaging and safety of surgical intervention. Eur. J. Obstet. Gynecol. Reprod. Biol. 226, 47–53 (2018).

    PubMed  Google Scholar 

  31. Zhang, S. P. et al. The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am. J. Pathol. 181, 1903–1910 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang, S. P. et al. Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy. Proc. Natl Acad. Sci. USA 111, 17266–17271 (2014).

    CAS  PubMed  Google Scholar 

  33. Coosemans, A. et al. The immune system as a biomarker in ovarian cancer diagnosis. Int. J. Gynecol. Cancer 27, 1428–1428 (2017).

    Google Scholar 

  34. Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. New Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  Google Scholar 

  35. Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Papa, S., van Schalkwyk, M. & Maher, J. Clinical evaluation of ErbB-targeted CAR T-Cells, following intracavity delivery in patients with ErbB-expressing solid tumors. Methods Mol. Biol. 1317, 365–382 (2015).

    PubMed  Google Scholar 

  37. Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2015).

    CAS  PubMed  Google Scholar 

  38. Smith, T. T. et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J. Clin. Invest. 127, 2176–2191 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. Kapoor, D. Nitinol for medical applications: a brief introduction to the properties and processing of nickel titanium shape memory alloys and their use in stents considerations for the manufacture of nitinol parts for stents and some other medical applications. Johnson Matthey Technol. Rev. 61, 66–76 (2017).

    Google Scholar 

  40. Huang, J. et al. Establishing a rabbit model of malignant esophagostenosis using the endoscopic implantation technique for studies on stent innovation. J. Transl. Med. 12, 12–40 (2014).

    Google Scholar 

  41. Zhang, F. et al. Nanoparticles that reshape the tumor milieu create a therapeutic window for effective T-cell therapy in solid malignancies. Cancer Res. 78, 3718–3730 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Fred Hutchinson Cancer Research Center’s Immunotherapy Initiative, with funds provided by the Bezos Family Foundation.

Author information

Author notes

  1. These authors contributed equally: Michael E. Coon, Sirkka B. Stephan.

Authors and Affiliations

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

    Michael E. Coon, Sirkka B. Stephan & Matthias T. Stephan

  2. Monarch Biosciences, Inc., Los Angeles, CA, USA

    Vikas Gupta & Colin P. Kealey

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

    Matthias T. Stephan

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

    Matthias T. Stephan

Authors
  1. Michael E. Coon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sirkka B. Stephan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vikas Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colin P. Kealey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias T. Stephan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.E.C. designed and performed experiments and analysed and interpreted data. S.B.S. functionalized thin films and stents. V.G. manufactured TFN micromeshes and stents. C.P.K. participated in experimental design and assisted with writing. M.T.S. designed the study, performed experiments, analysed and interpreted data, and wrote the manuscript.

Corresponding author

Correspondence to Matthias T. Stephan.

Ethics declarations

Competing interests

The Fred Hutchinson Cancer Center and M.T.S. have filed a patent pertaining to TFN-based micromeshes and stents for the delivery of tumour-specific T cells (PCT/US2017/067965), which was licensed by Monarch Biosciences. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Coon, M.E., Stephan, S.B., Gupta, V. et al. Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours. Nat Biomed Eng 4, 195–206 (2020). https://doi.org/10.1038/s41551-019-0486-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-019-0486-0

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