Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies

doi:10.1038/s41565-024-01781-4

. 2024 Dec;19(12):1914-1922.

doi: 10.1038/s41565-024-01781-4. Epub 2024 Sep 23.

Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies

Enbo Zhu^#^{1

2

3

4}, Jiaji Yu^#², Yan-Ruide Li², Feiyang Ma⁵, Yu-Chen Wang², Yang Liu¹, Miao Li², Yu Jeong Kim², Yichen Zhu², Zoe Hahn², Yang Zhou², James Brown², Yuchong Zhang², Matteo Pelegrini⁵, Tzung Hsiai^{3

4}, Lili Yang^{6

7

8

9}, Yu Huang^{10

11

12}

Affiliations

¹ Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁷ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁸ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁹ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
¹⁰ Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.
¹¹ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.
¹² California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.

^# Contributed equally.

PMID: 39313679
DOI: 10.1038/s41565-024-01781-4

Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies

Enbo Zhu et al. Nat Nanotechnol. 2024 Dec.

. 2024 Dec;19(12):1914-1922.

doi: 10.1038/s41565-024-01781-4. Epub 2024 Sep 23.

Authors

Affiliations

¹ Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁷ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁸ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁹ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
¹⁰ Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.
¹¹ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.
¹² California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA. yhuang@seas.ucla.edu.

^# Contributed equally.

PMID: 39313679
DOI: 10.1038/s41565-024-01781-4

Abstract

Chimeric antigen receptor (CAR)-engineered T cells represent a front-line therapy for cancers. However, the current CAR T cell manufacturing protocols do not adequately reproduce immunological synapse formation. Here, in response to this limitation, we have developed a flexible graphene oxide antigen-presenting platform (GO-APP) that anchors antibodies onto graphene oxide. By decorating anti-CD3 (αCD3) and anti-CD28 (αCD28) on graphene oxide (GO-APP^3/28), we achieved remarkable T cell proliferation. In vitro interactions between GO-APP^3/28 and T cells closely mimic the in vivo immunological synapses between antigen-presenting cells and T cells. This immunological synapse mimicry shows a high capacity for stimulating T cell proliferation while preserving their multifunctionality and high potency. Meanwhile, it enhances CAR gene-engineering efficiency, yielding a more than fivefold increase in CAR T cell production compared with the standard protocol. Notably, GO-APP^3/28 stimulated appropriate autocrine interleukin-2 (IL-2) in T cells and overcame the in vitro reliance on external IL-2 supplementation, offering an opportunity to culture T cell-based products independent of IL-2 supplementation.

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Conflict of interest statement

Competing interests: Y.H., L.Y., E.Z. and J.Y. are inventors on patents relating to this study filed by the University of California, Los Angeles. The other authors declare no competing interests.

References

1. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015). - PubMed - PMC - DOI
1. Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016). - PubMed - PMC - DOI
1. Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013). - PubMed - DOI
1. Huppa, J. B. & Davis, M. M. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–983 (2003). - PubMed - DOI
1. Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003). - PubMed - DOI

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[1] Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015). - PubMed - PMC - DOI

[2] Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015). - PubMed - PMC - DOI

[3] Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016). - PubMed - PMC - DOI

[4] Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016). - PubMed - PMC - DOI

[5] Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013). - PubMed - DOI

[6] Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013). - PubMed - DOI

[7] Huppa, J. B. & Davis, M. M. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–983 (2003). - PubMed - DOI

[8] Huppa, J. B. & Davis, M. M. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–983 (2003). - PubMed - DOI

[9] Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003). - PubMed - DOI

[10] Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003). - PubMed - DOI

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Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies

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Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies

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