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

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.

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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.

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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.

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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.

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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.

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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

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